Substituted indazoles, methods for the production thereof, pharmaceutical preparations that contain said new substituted indazoles, and use of said new substituted indazoles to produce drugs

ABSTRACT

The present application relates to novel substituted indazoles, to processes for preparation thereof, to the use thereof alone or in combinations for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of endometriosis and endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhoea, dyspareunia, dysuria and dyschezia, of lymphoma, rheumatoid arthritis, spondyloarthritis (especially psoriatic spondyloarthritis and Bekhterev&#39;s disease), lupus erythematosus, multiple sclerosis, macular degeneration, COPD, gout, fatty liver disorders, insulin resistance, neoplastic disorders and psoriasis.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patent Ser. No.17/009,553, filed Sep. 1, 2020, which is a continuation application ofU.S. patent application Ser. No. 16/377,025, filed on Apr. 5, 2019, nowU.S. Pat. No. 10,793,545, which is a continuation application of U.S.patent application Ser. No. 15/529,996, which adopts the internationalfiling date of Nov. 25, 2015, now U.S. Pat. No. 10,308,634, which is theNational Phase application under 35 U.S.C. § 371 oflntemationalApplication No. PCT/EP2015/077596, filed Nov. 25, 2015, which claimspriority benefit to European Application No. 14195032.9, filed Nov. 26,2014.

FIELD

The present application relates to novel substituted indazoles, toprocesses for preparation thereof, to intermediates for use in thepreparation of the novel compounds, to the use of the novel substitutedindazoles for treatment and/or prophylaxis of diseases and to the usethereof for production of medicaments for treatment and/or prophylaxisof diseases, especially of proliferative disorders, of autoimmunedisorders, of metabolic and inflammatory disorders, for examplerheumatoid arthritis, spondyloarthritis (especially psoriaticspondyloarthritis and Bekhterev's disease), chronic obstructivepulmonary disease (abbreviation: COPD), multiple sclerosis, systemiclupus erythematosus, gout, metabolic syndrome, fatty liver hepatitis,insulin resistance, endometriosis and inflammation-induced or chronicpain, and of lymphoma.

The present invention relates to novel substituted indazoles of thegeneral formula (I) which inhibit interleukin-1 receptor-associatedkinase 4 (IRAK4).

BACKGROUND

Human IRAK4 (interleukin-1 receptor-associated kinase 4) plays a keyrole in the activation of the immune system. Therefore, this kinase isan important therapeutic target molecule for the development ofinflammation-inhibiting substances. IRAK4 is expressed by a multitude ofcells and mediates the signal transduction of Toll-like receptors(TLRs), except TLR3, and receptors of the interleukin (IL)-1β familyconsisting of the IL-1R (receptor), IL-18R, IL-33R and IL-36R (Janewayand Medzhitov, Annu. Rev. Immunol., 2002; Dinarello, Annu. Rev.Immunol., 2009; Flannery and Bowie, Biochemical Pharmacology, 2010).

Neither IRAK4 knockout mice nor human cells from patients lacking IRAK4react to stimulation by TLRs (except TLR3) and the IL-1β family (Suzuki,Suzuki, et al., Nature, 2002; Davidson, Currie, et al., The Journal ofImmunology, 2006; Ku, von Bernuth, et al., JEM, 2007; Kim, Staschke, etal., JEM, 2007).

The binding of the TLR ligands or the ligands of the IL-1β family to therespective receptor leads to recruitment and binding of MyD88 [Myeloiddifferentiation primary response gene (88)] to the receptor. As aresult, MyD88 interacts with IRAK4, resulting in the formation of anactive complex which interacts with and activates the kinases IRAK1 orIRAK2 (Kollewe, Mackensen, et al., Journal of Biological Chemistry,2004; Precious et al., J. Biol. Chem., 2009). As a result of this, theNF (nuclear factor)-κB signalling pathway and the MAPK(mitogen-activated protein kinase) signal pathway is activated (Wang,Deng, et al., Nature, 2001). The activation both of the NF-κB signalpathway and of the MAPK signal pathway leads to processes associatedwith different immune processes. For example, there is increasedexpression of various inflammatory signal molecules and enzymes such ascytokines, chemokines and COX-2 (cyclooxygenase-2), and increased mRNAstability of inflammation-associated genes, for example COX-2, IL-6(interleukin-6), IL-8 (Holtmann, Enninga, et al., Journal of BiologicalChemistry, 2001; Datta, Novotny, et al., The Journal of Immunology,2004). Furthermore, these processes may be associated with theproliferation and differentiation of particular cell types, for examplemonocytes, macrophages, dendritic cells, T cells and B cells (Wan, Chi,et al., Nat Immunol, 2006; McGettrick and J. O'Neill, British Journal ofHaematology, 2007).

The central role of IRAK4 in the pathology of various inflammatorydisorders had already been shown by direct comparison of wild-type (WT)mice with genetically modified animals having a kinase-inactivated formof IRAK4 (IRAK4 KDKI). IRAK4 KDKI animals have an improved clinicalpicture in the animal model of multiple sclerosis, atherosclerosis,myocardial infarction and Alzheimer's disease (Rekhter, Staschke, etal., Biochemical and Biophysical Research Communication, 2008; Maekawa,Mizue, et al., Circulation, 2009; Staschke, Dong, et al., The Journal ofImmunology, 2009; Kim, Febbraio, et al., The Journal of Immunology,2011; Cameron, Tse, et al., The Journal of Neuroscience, 2012).Furthermore, it was found that deletion of IRAK4 in the animal modelprotects against virus-induced myocarditis by an improved anti-viralreaction with simultaneously reduced systemic inflammation (Valaperti,Nishii, et al., Circulation, 2013). It has also been shown that theexpression of IRAK4 correlates with the disease activity ofVogt-Koyanagi-Harada syndrome (Sun, Yang, et al., PLoS ONE, 2014). Inaddition, the high relevance of IRAK4 for immune complex-mediated IFNcc(interferon-alpha) production by plasmacytoid dendritic cells, a keyprocess in the pathogenesis of systemic lupus erythematosus (SLE), hasbeen shown (Chiang et al., The Journal of Immunology, 2010).Furthermore, the signalling pathway is associated with obesity (Ahmad,R., P. Shihab, et al., Diabetology & Metabolic Syndrome, 2015). As wellas the essential role of IRAK4 in congenital immunity, there are alsohints that IRAK4 influences the differentiation of Th17 T cells,components of adaptive immunity. In the absence of IRAK4 kinaseactivity, fewer IL-17-producing T cells (Th17 T cells) are generatedcompared to WT mice. The inhibition of IRAK4 enables the prophylaxisand/or treatment of atherosclerosis, type 1 diabetes mellitus,rheumatoid arthritis, spondyloarthritis (especially psoriaticspondyloarthritis and Bekhterev's disease), lupus erythematosus,psoriasis, vitiligo, giant cell arteritis, chronic inflammatory boweldisorder and viral disorders, for example HIV (human immunodeficiencyvirus), hepatitis virus (Staschke, et al., The Journal of Immunology,2009; Marquez, et al., Ann Rheum Dis, 2014; Zambrano-Zaragoza, et al.,International Journal of Inflammation, 2014; Wang, et al., Experimentaland Therapeutic Medicine, 2015; Ciccia, et al., Rheumatology, 2015).

Due to the central role of IRAK4 in the MyD88-mediated signal cascade ofTLRs (except TLR3) and the IL-1 receptor family, the inhibition of IRAK4can be utilized for the prophylaxis and/or treatment of disordersmediated by the receptors mentioned. TLRs and also components of theIL-1 receptor family are involved in the pathogenesis of rheumatoidarthritis, psoriasis, arthritis, myasthenia gravis, vasculitis, forexample Behcet's disease, granulomatosis with polyangiitis and giantcell arteritis, pancreatitis, systemic lupus erythematosus,dermatomyositis and polymyositis, metabolic syndrome including, forexample, insulin resistance, hypertension, dyslipoproteinaemia andobesity, diabetes mellitus (type 1 and type 2), diabetic nephropathy,osteoarthritis, Sjogren syndrome and sepsis (Yang, Tuzun, et al., JImmunol, 2005; Candia, Marquez et al., The Journal of Rheumatology,2007; Scanzello, Plaas, et al. Curr Opin Rheumatol, 2008; Deng,Ma-Krupa, et al., Circ Res, 2009; Roger, Froidevaux, et al, PNAS, 2009;Devaraj, Tobias, et al., Arterioscler Thromb Vasc Biol, 2011; Kim, Cho,et al., Clin Rheumatol, 2010; Carrasco et al., Clinical and ExperimentalRheumatology, 2011; Gambuzza, Licata, et al., Journal ofNeuroimmunology, 2011; Fresno, Archives Of Physiology And Biochemistry,2011; Volin and Koch, J Interferon Cytokine Res, 2011; Akash, Shen, etal., Journal of Pharmaceutical Sciences, 2012; Goh and Midwood,Rheumatology, 2012; Dasu, Ramirez, et al., Clinical Science, 2012;Ouziel, Gustot, et al., Am J Patho, 2012; Ramirez and Dasu, CurrDiabetes Rev, 2012, Okiyama et al., Arthritis Rheum, 2012; Chen et al.,Arthritis Research & Therapy, 2013; Holle, Windmoller, et al.,Rheumatology (Oxford), 2013; Li, Wang, et al., Pharmacology &Therapeutics, 2013; Sedimbi, Hagglof, et al., Cell Mol Life Sci, 2013;Caso, Costa, et al., Mediators of Inflammation, 2014; Cordiglieri,Marolda, et al., J Autoimmun, 2014; halal, Major, et al., J DiabetesComplications, 2014; Kaplan, Yazgan, et al., Scand J Gastroenterol,2014; Talabot-Aye, et al., Cytokine, 2014; Zong, Dorph, et al., AnnRheum Di, 2014; Ballak, Stienstra, et al., Cytokine, 2015; Timper,Seelig, et al., J Diabetes Complications, 2015). Skin diseases such aspsoriasis, atopic dermatitis, Kindler's syndrome, bullous pemphigoid,allergic contact dermatitis, alopecia areata, acne inversa and acnevulgaris are associated with the IRAK4-mediated TLR signalling pathwayas well as the IL-1R family (Schmidt, Mittnacht, et al., J Dermatol Sci,1996; Hoffmann, J Investig Dermatol Symp Proc, 1999; Gilliet, Conrad, etal., Archives of Dermatology, 2004; Niebuhr, Langnickel, et al.,Allergy, 2008; Miller, Adv Dermatol, 2008; Terhorst, Kalali, et al., AmJ Clin Dermatol, 2010; Viguier, Guigue, et al., Annals of InternalMedicine, 2010; Cevikbas, Steinhoff, J Invest Dermatol, 2012; Minkis,Aksentijevich, et al., Archives of Dermatology, 2012; Dispenza, Wolpert,et al., J Invest Dermatol, 2012; Minkis, Aksentijevich, et al., Archivesof Dermatology, 2012; Gresnigt and van de Veerdonk, Seminars inImmunology, 2013; Selway, Kurczab, et al., BMC Dermatology, 2013;Sedimbi, Hagglof, et al., Cell Mol Life Sci, 2013; Wollina, Koch, et al.Indian Dermatol Online, 2013; Foster, Baliwag, et al., The Journal ofImmunology, 2014).

Pulmonary disorders such as pulmonary fibrosis, obstructive pulmonarydisease (COPD), acute respiratory distress syndrome (ARDS), acute lunginjury (ALI), interstitial lung disease (ILD), sarcoidosis and pulmonaryhypertension also show an association with various TLR-mediated signalpathways. The pathogenesis of the pulmonary disorders may be eitherimpacted by infectious or non-infectious processes (Ramirez Cruz,Maldonado Bernal, et al., Rev Alerg Mex, 2004; Jeyaseelan, Chu, et al.,Infection and Immunity, 2005; Seki, Tasaka, et al., InflammationResearch, 2010; Xiang, Fan, et al., Mediators of Inflammation, 2010;Margaritopoulos, Antoniou, et al., Fibrogenesis & Tissue Repair, 2010;Hilberath, Carlo, et al., The FASEB Journal, 2011; Nadigel, Prefontaine,et al., Respiratory Research, 2011; Kovach and Standiford, InternationalImmunopharmacology, 2011; Bauer, Shapiro, et al., Mol Med, 2012; Deng,Yang, et al., PLoS One, 2013; Freeman, Martinez, et al., RespiratoryResearch, 2013; Dubaniewicz, A., Human Immunology, 2013). TLRs and IL-1Rfamily members are also involved in the pathogenesis of otherinflammatory disorders such as allergy, Behcet's disease, gout, lupuserythematosus, adult-onset Still's disease, pericarditis and chronicinflammatory bowel diseases such as ulcerative colitis and Crohn'sdisease, transplant rejection and graft-versus-host reaction, and soinhibition of IRAK4 here is a suitable prophylactic and/or therapeuticapproach (Liu-Bryan, Scott, et al., Arthritis & Rheumatism, 2005;Piggott, Eisenbarth, et al., J Clin Inves, 2005; Christensen, Shupe, etal., Immunity, 2006; Cario, Inflammatory Bowel Diseases, 2010;Nickerson, Christensen, et al., The Journal of Immunology, 2010;Rakoff-Nahoum, Hao, et al , Immunity, 2006; Heimesaat, Fischer, et al.,PLoS ONE, 2007; Heimesaat, Nogai, et al., Gut, 2010; Kobori, Yagi, etal., J Gastroenterol, 2010; Schmidt, Raghavan, et al., Nat Immunol,2010; Shi, Mucsi, et al , Immunological Reviews, 2010; Leventhal andSchroppel, Kidney Int, 2012; Chen, Lin, et al., Arthritis Res Ther,2013; Hao, Liu, et al., Curr Opin Gastroenterol, 2013; Kreisel andGoldstein, Transplant International, 2013; Li, Wang, et al.,Pharmacology & Therapeutics, 2013; Walsh, Carthy, et al., Cytokine &Growth Factor Reviews, 2013; Zhu, Jiang, et al., Autoimmunity, 2013; Yapand Lai, Nephrology, 2013; Vennegaard, Dyring-Andersen, et al., ContactDermatitis, 2014; D′Elia, Brucato, et al., Clin Exp Rheumatol, 2015;Jain, Thongprayoon, et al., Am J Cardiol., 2015; Li, Zhang, et al.,Oncol Rep., 2015).

Gynaecological disorders mediated by TLR and the IL-1R family, such asadenomyosis, dysmenorrhoea, dyspareunia and endometriosis, especiallyendometriosis-associated pain and other endometriosis-associatedsymptoms such as dysmenorrhoea, dyspareunia, dysuria and dyschezia, canbe positively influenced by the prophylactic and/or therapeutic use ofIRAK4 inhibitors (Akoum, Lawson, et al., Human Reproduction, 2007;Allhorn, Boing, et al., Reproductive Biology and Endocrinology, 2008;Lawson, Bourcier, et al., Journal of Reproductive Immunology, 2008;Sikora, Mielczarek-Palacz, et al., American Journal of ReproductiveImmunology, 2012; Khan, Kitajima, et al., Journal of Obstetrics andGynaecology Research, 2013; Santulli, Borghese, et al., HumanReproduction, 2013). The prophylactic and/or therapeutic use of IRAK4inhibitors can also have a positive influence on atherosclerosis(Seneviratne, Sivagurunathan, et al., Clinica Chimica Acta, 2012;Falck-Hansen, Kassiteridi, et al., International Journal of MolecularSciences, 2013; Sedimbi, Hagglof, et al., Cell Mol Life Sci, 2013).

In addition to the disorders already mentioned, IRAK4-mediated TLRprocesses have been described in the pathogenesis of eye disorders suchas retinal ischaemia, keratitis, allergic conjunctivitis,keratoconjunctivitis sicca, macular degeneration and uveitis(Kaarniranta and Salminen, J Mol Med (Berl), 2009; Sun and Pearlman,Investigative Ophthalmology & Visual Science, 2009; Redfern andMcDermott, Experimental Eye Research, 2010; Kezic, Taylor, et al., JLeukoc Biol, 2011; Chang, McCluskey, et al., Clinical & ExperimentalOphthalmology, 2012; Guo, Gao, et al , Immunol Cell Biol, 2012; Lee,Hattori, et al., Investigative Ophthalmology & Visual Science, 2012; Qi,Zhao, et al., Investigative Ophthalmology & Visual Science, 2014).

The inhibition of IRAK4 is also a suitable therapeutic approach forfibrotic disorders, for example hepatic fibrosis, myocarditis, primarybiliary cirrhosis, cystic fibrosis (Zhao, Zhao, et al., Scand JGastroenterol, 2011; Benias, Gopal, et al., Clin Res HepatolGastroenterol, 2012; Yang, L. and E. Seki, Front Physiol, 2012; Liu, Hu,et al., Biochim Biophys Acta., 2015).

By virtue of the key position that IRAK4 has in disorders mediated byTLR- and the IL-1R family, it is possible to treat chronic liverdisorders, for example fatty liver hepatitis and especiallynon-alcoholic fatty liver disease (NAFLD) and/or non-alcoholicsteatohepatitis (NASH), alcoholic steatohepatitis (ASH) in apreventative and/or therapeutic manner with IRAK4 inhibitors (Nozaki,Saibara, et al., Alcohol Clin Exp Res, 2004; Csak, T., A. Velayudham, etal., Am J Physiol Gastrointest Liver Physiol, 2011; Miura, Kodama, etal., Gastroenterology, 2010; Kamari, Shaish, et al., J Hepatol, 2011;Ye, Li, et al., Gut, 2012; Roh, Seki, J Gastroenterol Hepatol, 2013;Ceccarelli, S., V. Nobili, et al., World J Gastroenterol, 2014; Miura,Ohnishi, World J Gastroenterol, 2014; Stojsavljevic, Palcic, et al.,World J Gastroenterol, 2014).

Because of the central role of IRAK4 in TLR-mediated processes, theinhibition of IRAK4 also enables the treatment and/or prevention ofcardiovascular and neurological disorders, for example myocardialreperfusion damage, myocardial infarction, hypertension (Oyama, Blais,et al., Circulation, 2004; Timmers, Sluijter, et al., CirculationResearch, 2008; Fang and Hu, Med Sci Monit, 2011; Bijani, InternationalReviews of Immunology, 2012; Bomfim, Dos Santos, et al., Clin Sci(Lond), 2012; Christia and Frangogiannis, European Journal of ClinicalInvestigation, 2013; Thompson and Webb, Clin Sci (Lond), 2013; Hernanz,Martinez-Revelles, et al., British Journal of Pharmacology, 2015;Frangogiannis, Curr Opin Cardiol, 2015; Bomfim, Echem, et al., LifeSciences, 2015), and also Alzheimer's disease, stroke, craniocerebraltrauma, amyotrophic lateral sclerosis (ALS) and Parkinson's (Brough,Tyrrell, et al., Trends in Pharmacological Sciences, 2011; Carty andBowie, Biochemical Pharmacology, 2011; Denes, Kitazawa, Cheng, et al.,The Journal of Immunology, 2011; Lim, Kou, et al., The American Journalof Pathology, 2011; Béraud and Maguire-Zeiss, Parkinsonism & RelatedDisorders, 2012; Denes, Wilkinson, et al., Disease Models & Mechanisms,2013; Noelker, Morel, et al., Sci. Rep., 2013; Wang, Wang, et al.,Stroke, 2013; Xiang, Chao, et al., Rev Neurosci, 2015; Lee, Lee, et al.,J Neuroinflammation, 2015).

Because of the involvement of TLR-mediated signals and IL-1 receptorfamily-mediated signals via IRAK4 in the case of pruritus and pain,including acute, chronic, inflammatory and neuropathic pain, there maybe assumed to be a therapeutic effect in the indications mentionedthrough the inhibition of IRAK4. Examples of pain include hyperalgesia,allodynia, premenstrual pain, endometriosis-associated pain,post-operative pain, interstitial cystitis, CRPS (complex regional painsyndrome), trigeminal neuralgia, prostatitis, pain caused by spinal cordinjury, inflammation-induced pain, lower back pain, cancer pain,chemotherapy-associated pain, HIV treatment-induced neuropathy,burn-induced pain and chronic pain (Wolf, Livshits, et al., Brain,Behavior, and Immunity, 2008; Kim, Lee, et al., Toll-like Receptors:Roles in Infection and Neuropathology, 2009; del Rey, Apkarian, et al.,Annals of the New York Academy of Sciences, 2012; Guerrero, Cunha, etal., European Journal of Pharmacology, 2012; Kwok, Hutchinson, et al.,PLoS ONE, 2012; Nicotra, Loram, et al., Experimental Neurology, 2012;Chopra and Cooper, J Neuroimmune Pharmacol, 2013; David, Ratnayake, etal., Neurobiology of Disease, 2013; Han, Zhao, et al., Neuroscience,2013; Liu and Ji, Pflugers Arch., 2013; Stokes, Cheung, et al., Journalof Neuroinflammation, 2013; Zhao, Zhang, et al., Neuroscience, 2013;Liu, Zhang, et al., Cell Research, 2014; Park, Stokes, et al., CancerChemother Pharmacol, 2014; Van der Watt, Wilkinson, et al., BMC InfectDis, 2014; Won, K. A., M. J. Kim, et al., J Pain, 2014; Min, Ahmad, etal., Photochem Photobiol., 2015; Schrepf, Bradley, et al., Brain BehavImmun, 2015; Wong, L., J. D. Done, et al., Prostate, 2015).

This also applies to some oncological disorders. Particular lymphomas,for example ABC-DLBCL (activated B-cell diffuse large-cell B-celllymphoma), mantle cell lymphoma and Waldenstrom's disease, and alsochronic lymphatic leukaemia, melanoma, pancreatic tumour and liver cellcarcinoma, are characterized by mutations in MyD88 or changes in MyD88activity which can be treated by an IRAK4 inhibitor (Ngo, Young, et al.,Nature, 2011; Puente, Pinyol, et al., Nature, 2011; Ochi, Nguyen, etal., J Exp Med, 2012; Srivastava, Geng, et al., Cancer Research, 2012;Treon, Xu, et al., New England Journal of Medicine, 2012; Choi, Kim, etal., Human Pathology, 2013; (Liang, Chen, et al., Clinical CancerResearch, 2013). In addition, MyD88 plays an important role inras-dependent tumours, and so IRAK4 inhibitors are also suitable fortreatment thereof (Kfoury, A., K. L. Corf, et al., Journal of theNational Cancer Institute, 2013). There can also be assumed to be atherapeutic effect in breast cancer, ovarian carcinoma, colorectalcarcinoma, head and neck carcinoma, lung cancer, prostate cancer throughthe inhibition of IRAK4, since the indications mentioned are associatedwith the signalling pathway (Szczepanski, Czystowska, et al., CancerRes, 2009; Zhang, He, et al., Mol Biol Rep, 2009; Wang, Qian, et al., BrJ Cancer Kim, 2010; Jo, et al., World J Surg Oncol, 2012; Zhao, Zhang,et al.; Front Immunol, 2014; Chen, Zhao, et al., Int J Clin Exp Pathol,2015).

Inflammatory disorders such as CAPS (cryopyrin-associated periodicsyndromes) including FCAS (familial cold autoinflammatory syndrome), MWS(Muckle-Wells syndrome), NOMID (neonatal-onset multisystem inflammatorydisease) and CONCA (chronic infantile, neurological, cutaneous, andarticular) syndrome; FMF (familial mediterranean fever), HIDS (hyper-IgDsyndrome), TRAPS (tumour necrosis factor receptor 1-associated periodicsyndrom), juvenile idiopathic arthritis, adult-onset Still's disease,Adamantiades-Behcet's disease, rheumatoid arthritis, osteoarthritis,keratoconjunctivitis sicca, PAPA syndrome (pyogenic arthritis, Pyodermagangraenosum and acne), Schnitzler's syndrome and Sjogren syndrome aretreated by blocking the IL-1 signal pathway; therefore here, too, anIRAK4 inhibitor is suitable for treatment of the diseases mentioned(Narayanan, Corrales, et al., Cornea, 2008; Brenner, Ruzicka, et al.,British Journal of Dermatology, 2009; Henderson and Goldbach-Mansky,Clinical Immunology, 2010; Dinarello, European Journal of Immunology,2011; Gul, Tugal-Tutkun, et al., Ann Rheum Dis, 2012; Pettersson, Annalsof MedicinePetterson, 2012; Ruperto, Brunner, et al., New EnglandJournal of Medicine, 2012; Nordstrom, Knight, et al., The Journal ofRheumatology, 2012; Vijmasi, Chen, et al., Mol Vis, 2013; Yamada,Arakaki, et al., Opinion on Therapeutic Targets, 2013; de Koning, ClinTransl Allergy, 2014). The ligand of IL-33R, IL-33, is involvedparticularly in the pathogenesis of acute kidney failure, and so theinhibition of IRAK4 for prophylaxis and/or treatment is a suitabletherapeutic approach (Akcay, Nguyen, et al., Journal of the AmericanSociety of Nephrology, 2011). Components of the IL-1 receptor family areassociated with myocardial infarction, different pulmonary disorderssuch as asthma, COPD, idiopathic interstitial pneumonia, allergicrhinitis, pulmonary fibrosis and acute respiratory distress syndrome(ARDS), and so prophylactic and/or therapeutic action is to be expectedin the indications mentioned through the inhibition of IRAK4 (Kang,Homer, et al., The Journal of Immunology, 2007; Imaoka, Hoshino, et al.,European Respiratory Journal, 2008; Couillin, Vasseur, et al., TheJournal of Immunology, 2009; Abbate, Kontos, et al., The AmericanJournal of Cardiology, 2010; Lloyd, Current Opinion in Immunology, 2010;Pauwels, Bracke, et al., European Respiratory Journal, 2011; Haenuki,Matsushita, et al., Journal of Allergy and Clinical Immunology, 2012;Yin, Li, et al., Clinical & Experimental Immunology, 2012; Abbate, VanTassell, et al., The American Journal of Cardiology, 2013;Alexander-Brett, et al., The Journal of Clinical Investigation, 2013;Bunting, Shadie, et al., BioMed Research International, 2013; Byers,Alexander-Brett, et al., The Journal of Clinical Investigation, 2013;Kawayama, Okamoto, et al., J Interferon Cytokine Res, 2013;Martinez-Gonzalez, Roca, et al., American Journal of Respiratory Celland Molecular Biology, 2013; Nakanishi, Yamaguchi, et al., PLoS ONE,2013; Qiu, Li, et al., Immunology, 2013; Li, Guabiraba, et al., Journalof Allergy and Clinical Immunology, 2014; Saluja, Ketelaar, et al.,Molecular Immunology, 2014; Lugrin, Parapanov, et al., The Journal ofImmunology, 2015).

The prior art discloses a multitude of IRAK4 inhibitors (see, forexample, Annual Reports in Medicinal Chemistry (2014), 49, 117-133).

U.S. Pat. No. 8,293,923 and US20130274241 disclose IRAK4 inhibitorshaving a 3-substituted indazole structure. There is no description of2-substituted indazoles.

WO2013106254 and WO2011153588 disclose 2,3-disubstituted indazolederivatives.

WO2007091107 describes 2-substituted indazole derivatives for thetreatment of Duchenne muscular dystrophy. The compounds disclosed do nothave 6-hydroxyalkyl substitution.

WO2015091426 describes indazoles, such as Example 64, substituted at the2 position by a carboxamide side chain

EXAMPLE 64

WO2015104662 discloses 2-substituted indazoles of the following generalformula:

in which R₂ is an alkyl or cycloalkyl group. There are explicitdescriptions of 2-substituted indazoles having a methyl, 2-methoxyethyland cyclopentyl group at the 2 position (Examples 1, 4 and 76). Alsodescribed by Example 117 is an indazole derivative having a hydroxyethylsubstituent at the 1 position. However, no indazole derivatives having a3-hydroxy-3-methylbutyl substituent at the 1 position or 2 position aredescribed.

Indazoles having a hydroxyl-substituted alkyl group in the 2 positionare encompassed generically by the general formula, but are notdisclosed explicitly in WO2015104662.

Indazoles having an alkyl group in the 2 position where the alkyl groupis additionally substituted by a methylsulphonyl group are notencompassed by the general formula and the definitions of the R₂substituents in WO2015104662.

In addition to the above-described substitution pattern on the indazolein 1 and 2 positions, WO2015104662 describes indazoles havingsubstitution at the 6 position for which R₁ is defined as follows:alkyl, cyano, —NR_(a)R_(b) or optionally substituted groups selectedfrom cycloalkyl, aryl or heterocyclyl, where the substituents areindependently alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl, amino,aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, —OCOCH₂—O-alkyl,—OP(O)(O-alkyl)₂ or —CH₂—OP(O)(O-alkyl)₂. For imidazole compounds inwhich R₁ is an alkyl group, the effective filing date is 7 Jan. 2015(international filing date of WO2015104662). The Indian applications146/CHE/2014 and 3018/CHE/2014 whose priority is claimed do not discloseany indazole compounds for which R₁ is an alkyl group.

Thus, indazole compounds of the following general formula:

in which R₁ is an optionally substituted alkyl group are described forthe first time on 7 Jan. 2015 and hence after the priority date of thepresent application.

Examples of substituents at the 6 position described in WO2015104662 forR₁ are cyclopropyl, cyclohexyl, cyano, 3-fluorophenyl and saturatedheterocyclic substituents. Indazoles having a hydroxyl-substituted alkylgroup at position 6 are not described explicitly in WO2015104662.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 : Inhibition of IL-23 in human monocyte-generated DCs for ExampleCompound 12. Data are shown as mean values with standard deviations.

FIG. 2A and FIG. 2B: Inhibition of INF-α in (A) imiquimod (R837)- or (B)CpG-A-stimulated human plasmacytoid DCs for Example Compound 12. Dataare shown as mean values with standard deviations.

FIG. 3 : Treatment of an LPS-induced inflammation with Example Compound11 leads to a reduced amount of secreted TNF-α. Data are shown as meanvalues with standard deviations.

FIG. 4A: Treatment of an IL-1β-induced inflammation with ExampleCompound 11 leads to a dose-dependent reduction in the amount ofsecreted TNF-α. Data are shown as mean values with standard deviations.

FIG. 4B: Treatment of an IL-1β-induced inflammation with ExampleCompound 12 leads to a dose-dependent reduction in the amount ofsecreted TNF-α. Data are shown as mean values with standard deviations.

FIG. 5 : Anti-inflammatory effects of Example Compound 11 in an animalmodel of rheumatoid arthritis (adjuvant-induced rat model). Significantand dose-dependent inhibition of rheumatic joint inflammation measuredon the basis of the disease activity score. The data corresponds to themean values+standard deviations. Single-factor ANOVA variance analysiswith subsequent multiple comparative analysis with the CFA control groupby means of Dunnett's test; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.

FIG. 6 : Anti-inflammatory effects of Example Compound 12 in an animalmodel of rheumatoid arthritis (collagen antibody-induced mouse model).Significant and dose-dependent inhibition of rheumatic jointinflammation measured on the basis of the disease activity score. Thedata corresponds to the mean values+standard deviations. The statisticalsignificances between collagen antibody (AK) control and the treatmentgroups were calculated by means of single-factor ANOVA variance analysiswith subsequent multiple comparative analysis (Dunnett's test) (*p<0.05;**p<0.01; ***p<0.001; ****p<0.0001).

DETAILED DESCRIPTION

The problem addressed by the present invention is that of providingnovel compounds that act as inhibitors of interleukin-1 receptorassociated kinase-4 (IRAK4).

The novel IRAK4 inhibitors are especially suitable for treatment and forprevention of proliferative, metabolic and inflammatory disorderscharacterized by an overreacting immune system. Particular mentionshould be made here of inflammatory skin disorders, cardiovasculardisorders, lung disorders, eye disorders, neurological disorders, paindisorders and cancer.

In addition, the novel IRAK4 inhibitors are suitable for treatment andprevention

-   -   of autoimmune and inflammatory disorders, especially rheumatoid        arthritis, multiple sclerosis, systemic lupus erythematosus,        spondyloarthritis and gout,    -   of metabolic disorders, especially hepatic disorders such as        fatty liver, and    -   of gynaecological disorders, especially of endometriosis and of        endometriosis-associated pain and other endometriosis-associated        symptoms such as dysmenorrhoea, dyspareunia, dysuria and        dyschezia.

The present invention provides compounds of the general formula (I)

in which:

-   R¹ is C₁-C₆-alkyl, where the C₁-C₆-alkyl group is unsubstituted or    mono- or polysubstituted identically or differently by halogen,    hydroxyl, an unsubstituted or mono- or poly-halogen-substituted    C₃-C₆-cycloalkyl, or an R⁶, R⁷SO₂, R⁷SO or R⁸O group,    -   or a group selected from:

-   -   where * represents the bonding site of the group to the rest of        the molecule;

-   R² and R³ always have the same definition and are both either    hydrogen or C₁-C₆-alkyl;

-   R⁴ is halogen, cyano, an unsubstituted or a singly or multiply,    identically or differently substituted C₁-C₆-alkyl or an    unsubstituted or a singly or multiply, identically or differently    substituted C₃-C₆-cycloalkyl, and the substituents are selected from    the group of halogen and hydroxyl;

-   R⁵ is hydrogen, halogen or an unsubstituted or mono- or    poly-halogen-substituted C₁-C₆-alkyl;

-   R⁶ is an unsubstituted or mono- or di-methyl-substituted monocyclic    saturated heterocycle having 4 to 6 ring atoms, which contains a    heteroatom or a heterogroup from the group of O, S, SO and SO₂;

-   R⁷ is C₁-C₆-alkyl, where the C₁-C₆-alkyl group is unsubstituted or    mono- or polysubstituted identically or differently by halogen,    hydroxyl or C₃-C₆-cycloalkyl, or R⁷ is C₃-C₆-cycloalkyl;

-   R⁸ is C₁-C₆-alkyl, where the C₁-C₆-alkyl group is unsubstituted or    mono- or polysubstituted identically or differently by halogen;

and the diastereomers, enantiomers, metabolites, salts, solvates orsolvates of the salts thereof.

In the case of the synthesis intermediates and working examples of theinvention described hereinafter, any compound specified in the form of asalt of the corresponding base or acid is generally a salt of unknownexact stoichiometric composition, as obtained by the respectivepreparation and/or purification process. Unless specified in moredetail, additions to names and structural formulae, such as“hydrochloride”, “trifluoroacetate”, “sodium salt” or “x HCl”, “xCF₃COOH”, “x Na⁺” should not therefore be understood in a stoichiometricsense in the case of such salts, but have merely descriptive characterwith regard to the salt-forming components present therein.

This applies correspondingly if synthesis intermediates or workingexamples or salts thereof were obtained in the form of solvates, forexample hydrates, of unknown stoichiometric composition (if they are ofa defined type) by the preparation and/or purification processesdescribed.

Inventive compounds are the compounds of the formula (I) and the salts,solvates and solvates of the salts thereof, the compounds that areencompassed by formula (I) and are of the formulae mentioned below andthe salts, solvates and solvates of the salts thereof and the compoundsthat are encompassed by the formula (I) and are mentioned below asembodiments and the salts, solvates and solvates of the salts thereof ifthe compounds that are encompassed by the formula (I) and are mentionedbelow are not already salts, solvates and solvates of the salts.

Preferred salts in the context of the present invention arephysiologically acceptable salts of the inventive compounds. However,the invention also encompasses salts which themselves are unsuitable forpharmaceutical applications but which can be used, for example, for theisolation or purification of the inventive compounds.

Physiologically acceptable salts of the inventive compounds include acidaddition salts of mineral acids, carboxylic acids and sulphonic acids,for example salts of hydrochloric acid, hydrobromic acid, sulphuricacid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid,toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonicacid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid,tartaric acid, malic acid, citric acid, fumaric acid, maleic acid andbenzoic acid.

Physiologically acceptable salts of the inventive compounds also includesalts of conventional bases, by way of example and with preferencealkali metal salts (e.g. sodium and potassium salts), alkaline earthmetal salts (e.g. calcium and magnesium salts) and ammonium saltsderived from ammonia or organic amines having 1 to 16 carbon atoms, byway of example and with preference ethylamine, diethylamine,triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine,dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine andN-methylpiperidine.

Solvates in the context of the invention are described as those forms ofthe inventive compounds which form a complex in the solid or liquidstate by coordination with solvent molecules. Hydrates are a specificform of the solvates in which the coordination is with water.

The inventive compounds may, depending on their structure, exist indifferent stereoisomeric forms, i.e. in the form of configurationalisomers or else, if appropriate, of conformational isomers (enantiomersand/or diastereomers, including those in the case of atropisomers). Thepresent invention therefore encompasses the enantiomers anddiastereomers, and the respective mixtures thereof. Thestereoisomerically homogeneous constituents can be isolated from suchmixtures of enantiomers and/or diastereomers in a known manner;chromatography processes are preferably used for this purpose,especially HPLC chromatography on an achiral or chiral phase.

If the inventive compounds can occur in tautomeric forms, the presentinvention encompasses all the tautomeric forms.

The present invention also encompasses all suitable isotopic variants ofthe inventive compounds.

An isotopic variant of an inventive compound is understood here asmeaning a compound in which at least one atom within the inventivecompound has been exchanged for another atom of the same atomic number,but with a different atomic mass than the atomic mass which usually orpredominantly occurs in nature. Examples of isotopes which can beincorporated into an inventive compound are those of hydrogen, carbon,nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine andiodine, such as 2H (deuterium), 3H (tritium), 13C, 14C, 15N, 17O, 18O,32P, 33P, 33S, 34S, 35S, 36S, 18F, 36Cl, 82Br, 123I, 124I, 129I and131I. Particular isotopic variants of an inventive compound, such as, inparticular, those in which one or more radioactive isotopes have beenincorporated, may be beneficial, for example, for the examination of themechanism of action or of the active ingredient distribution in thebody; because of the comparative ease of preparability anddetectability, particularly compounds labelled with 3H or 14C isotopesare suitable for this purpose. In addition, the incorporation ofisotopes, for example of deuterium, may lead to particular therapeuticbenefits as a consequence of greater metabolic stability of thecompound, for example an extension of the half-life in the body or areduction in the active dose required; such modifications of theinventive compounds may therefore in some cases also constitute apreferred embodiment of the present invention. Isotopic variants of theinventive compounds can be prepared by the processes known to thoseskilled in the art, for example by the methods described further belowand the procedures described in the working examples, by usingcorresponding isotopic modifications of the respective reagents and/orstarting compounds.

The present invention further provides all the possible crystalline andpolymorphous forms of the inventive compounds, where the polymorphs maybe present either as single polymorphs or as a mixture of a plurality ofpolymorphs in all concentration ranges.

The present invention additionally also encompasses prodrugs of theinventive compounds. The term “prodrugs” in this context refers tocompounds which may themselves be biologically active or inactive butare converted (for example metabolically or hydrolytically) to inventivecompounds during their residence time in the body.

In the context of the present invention, unless specified otherwise, thesubstituents have the following meanings:

Alkyl in the context of the invention represents a straight-chain orbranched alkyl group having the particular number of carbon atomsspecified. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, n-pentyl,1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,2,2-dimethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl and 2-ethylbutyl.Preference is given to methyl, ethyl, n-propyl, n-butyl, 2-methylbutyl,3-methylbutyl and 2,2-dimethylpropyl.

Cycloalkyl in the context of the invention is a monocyclic saturatedalkyl group having the number of carbon atoms specified in each case.Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

Alkoxy in the context of the invention represents a straight-chain orbranched alkoxy group having the particular number of carbon atomsspecified. 1 to 6 carbon atoms are preferred. Examples include methoxy,ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy,tert-butoxy, n-pentoxy, isopentoxy, 1-ethylpropoxy, 1-methylbutoxy,2-methylbutoxy, 3-methylbutoxy and n-hexoxy. Particular preference isgiven to a linear or branched alkoxy group having 1 to 4 carbon atoms.Examples which may be mentioned as being preferred are methoxy, ethoxy,n-propoxy, 1-methylpropoxy, n-butoxy and isobutoxy.

Halogen in the context of the invention is fluorine, chlorine andbromine. Preference is given to fluorine.

Hydroxyl in the context of the invention is OH.

A monocyclic saturated heterocycle is a monocyclic saturated heterocyclewhich has 4 to 6 ring atoms and contains a heteroatom or a heterogroupfrom the group of 0, S, SO and SO₂. A heterocycle having a heteroatom ora heterogroup from the group of O, SO and SO₂ is preferred. Examplesinclude: oxetane, tetrahydrofuran, tetrahydro-2H-pyran-4-yl,1,1-dioxidotetrahydro-2H-thiopyran-3-yl,1,1-dioxidotetrahydro-2H-thiopyran-2-yl,1,1-dioxidotetrahydro-2H-thiopyran-4-yl,1,1-dioxidotetrahydrothiophen-3-yl, 1,1-dioxidotetrahydrothiophen-2-yl,1,1-dioxidothietan-2-yl or 1,1-dioxidothietan-3-yl. Particularpreference is given here to oxetane and tetrahydrofuran. Very particularpreference is given to oxetan-3-yl.

A symbol * at a bond denotes the bonding site in the molecule.

When groups in the inventive compounds are substituted, the groups maybe mono- or polysubstituted, unless specified otherwise. In the contextof the present invention, all groups which occur more than once aredefined independently of one another. Substitution by one, two or threeidentical or different substituents is preferred.

A preferred embodiment of R¹ is a C₂-C₆-alkyl group substituted by 1, 2or 3 fluorine atoms. Particular preference is given to2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl and 4,4,4-trifluorobutyl.Very particular preference is given to a 4,4,4-trifluorobutyl group.

A further preferred embodiment of R¹ is a C₂-C₆-alkyl group substitutedby one or two hydroxyl group(s) or one C₁-C₃-alkoxy or atri-fluorine-substituted C₁-C₃-alkoxy. Particular preference is given toa C₂-C₅-alkyl group substituted by hydroxyl or C₁-C₃-alkoxy ortrifluoromethoxy or 2,2,2-trifluoroethoxy. Very particular preference isgiven to 3-hydroxy-3-methylbutyl, 3-methoxypropyl, 3-hydroxypropyl,3-trifluoromethoxypropyl, 2-methoxyethyl or 2-hydroxyethyl. Especiallypreferred is the 3-hydroxy-3-methylbutyl group.

Further preferably, R¹ is a C₂-C₆-alkyl group substituted by aC₁-C₆-alkyl-SO₂ group. A methyl-SO₂-substituted C₂-C₄-alkyl group isparticularly preferred. Especially preferred for R¹ are2-(methylsulphonyl)ethyl or 3-(methylsulphonyl)propyl. From the lattergroup, 2-(methylsulphonyl)ethyl is particularly preferred.

Additionally preferably, R¹ is a C₁-C₃-alkyl group substituted byoxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyran-4-yl,1,1-dioxidotetrahydro-2H-thiopyran-3-yl,1,1-dioxidotetrahydro-2H-thiopyran-2-yl,1,1-dioxidotetrahydro-2H-thiopyran-4-yl,1,1-dioxidotetrahydrothiophen-3-yl, 1,1-dioxidotetrahydrothiophen-2-yl,1,1-dioxidothietan-2-yl or 1,1-dioxidothietan-3-yl. Particularpreference is given to a C₁-C₃-alkyl group substituted by an oxetanegroup. Especially preferred for R¹ is an oxetan-3-ylmethyl group.

For R² and R³, which always have the same definition, hydrogen or methylare preferred. Methyl is particularly preferred.

In the case of R⁴, preference is given to an unsubstituted or mono- orpoly-halogen-substituted C₁-C₃-alkyl group or a C₁-C₃-alkyl groupsubstituted by one hydroxyl group or a C₁-C₃-alkyl group substituted byone hydroxyl group and three fluorine atoms.

For R⁴, particular preference is given to the following groups: methyl,ethyl, trifluoro-C₁-C₃-alkyl, difluoro-C₁-C₃-alkyl, hydroxymethyl,1-hydroxyethyl, 2-hydroxypropan-2-yl and 2,2,2-trifluoro-1-hydroxyethyl.For R⁴, particular preference is given to the methyl, trifluoromethyland difluoromethyl groups. Particular preference is given here to atrifluoromethyl group.

A preferred embodiment of R⁵ is hydrogen, fluorine, chlorine orC₁-C₃-alkyl. More preferably, R⁵ is hydrogen, fluorine or methyl. Mostpreferably, R⁵ is hydrogen or fluorine.

Particular preference is also given to compounds in which R⁴ is methylor trifluoromethyl and R⁵ is fluorine. Very particular preference isgiven to compounds in which R⁴ is methyl and R⁵ is fluorine, where R⁵ isin the ortho position to R⁴.

For R⁶, preferred embodiments include oxetanyl, tetrahydrofuranyl,tetrahydro-2H-pyran-4-yl, 1,1-dioxidotetrahydro-2H-thiopyran-3-yl,1,1-dioxidotetrahydro-2H-thiopyran-2-yl,1,1-dioxidotetrahydro-2H-thiopyran-4-yl,1,1-dioxidotetrahydrothiophen-3-yl, 1,1-dioxidotetrahydrothiophen-2-yl,1,1-dioxidothietan-2-yl or 1,1-dioxidothietan-3-yl. Particularpreference is given here to oxetanyl. Very particular preference isgiven to oxetan-3-yl.

R⁷ is exclusively connected to the functional groups —SO₂— and —SO—,i.e. is an le-substituted —SO₂— or SO group. In this connection, R⁷ ispreferably C₁-C₄-alkyl, where the C₁-C₄-alkyl group is unsubstituted ormonosubstituted by hydroxyl or by cyclopropyl or substituted by threefluorine atoms. Additionally preferred for R⁷ is a cyclopropyl group.Particularly preferred for R⁷ are methyl, ethyl or hydroxyethyl. Veryparticular preference is given to methyl for R⁷.

This means that, in the case of a C₁-C₆-alkyl group substituted byR⁷SO₂— or R⁷SO—, in the context of R¹, preference is given to aC₁-C₆-alkyl substituted by a C₁-C₆-alkyl-SO₂ or a C₁-C₆-alkyl-SO. ForR¹, preference is given here especially to methylsulphonylethyl andmethylsulphonylpropyl. Very particular preference is given here tomethylsulphonylethyl.

For R⁸, preference is given to an unsubstituted C₁-C₄-alkyl group or atri-fluorine-substituted C₁-C₄-alkyl group. Particular preference isgiven to methyl, ethyl, trifluoromethyl or 2,2,2-trifluoroethyl. Veryparticular preference is given to methyl, trifluoromethyl or2,2,2-trifluoroethyl.

Preference is given to compounds of the formula (I) in which

-   R¹ is C₁-C₆-alkyl, where the C₁-C₆-alkyl group is unsubstituted or    mono- or polysubstituted identically or differently by fluorine,    hydroxyl or an R⁶, R⁷SO₂, R⁷SO or R⁸O group;-   R² and R³ always have the same definition and are both either    hydrogen or C₁-C₃-alkyl;-   R⁴ is halogen, cyano or C₁-C₃-alkyl, where the C₁-C₃-alkyl group is    unsubstituted or mono- or polysubstituted identically or differently    by halogen or hydroxyl;-   R⁵ is hydrogen, fluorine, chlorine or C₁-C₃-alkyl;-   R⁶ is oxetanyl or tetrahydrofuranyl;-   R⁷ is C₁-C₄-alkyl, where the C₁-C₄-alkyl group is unsubstituted or    monosubstituted by hydroxyl or by cyclopropyl or substituted by    three fluorine atoms;-   R⁸ is unsubstituted C₁-C₄-alkyl or tri-fluorine-substituted    C₁-C₄-alkyl;

and the diastereomers, enantiomers, metabolites, salts, solvates orsolvates of the salts thereof.

Preference is additionally given to compounds of the formula (I) inwhich

-   R¹ is C₂-C₆-alkyl, where C₂-C₆-alkyl is unsubstituted, or    C₂-C₆-alkyl is mono-, di- or tri-fluorine-substituted or C₂-C₆-alkyl    is monosubstituted by hydroxyl, R⁶, R⁷SO₂, or R⁸O, or in which R¹ is    an oxetanyl-substituted C₁-C₃-alkyl;-   R² and R³ always have the same definition and are both either    hydrogen or methyl;-   R⁴ is an unsubstituted or mono- or poly-halogen-substituted    C₁-C₃-alkyl group or a C₁-C₃-alkyl group substituted by one hydroxyl    group or a C₁-C₃-alkyl group substituted by one hydroxyl group and    three fluorine atoms;

R⁵ is hydrogen, fluorine or C₁-C₃-alkyl;

R⁷ is C₁-C₃-alkyl;

R⁸ is C₁-C₄-alkyl, where the C₁-C₄-alkyl group is unsubstituted ormono-, di- or tri-fluorine-substituted;

and the diastereomers, enantiomers, metabolites, salts, solvates orsolvates of the salts thereof.

Particular preference is also given to compounds of the general formula(I) in which

R¹ is a C₂-C₅-alkyl group substituted by hydroxyl or C₁-C₃-alkoxy ortrifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl or is amethyl-SO₂-substituted C₂-C₄-alkyl group or is anoxetan-3-yl-substituted C₁-C₂-alkyl group;

-   R² and R³ always have the same definition and are both hydrogen or    methyl;-   R⁴ is methyl, ethyl, trifluoro-C₁-C₃-alkyl, difluoro-C₁-C₃-alkyl,    hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl and    2,2,2-trifluoro-1-hydroxyethyl and-   R⁵ is hydrogen, fluorine or methyl;

and the diastereomers, enantiomers, metabolites, salts, solvates orsolvates of the salts thereof.

Very particular preference is given to compounds in which

-   R¹ is 4,4,4-trifluorobutyl, 3-hydroxy-3-methylbutyl, 3-hydroxybutyl,    3-methoxypropyl, 3-hydroxypropyl, 3-hydroxy-2-methylpropyl,    3-hydroxy-2,2-dimethylpropyl, 3-trifluoromethoxypropyl,    2-methoxyethyl, 2-hydroxyethyl, 2-(methylsulphonyl)ethyl or    3-(methylsulphonyl)propyl;-   R² and R³ are both methyl or hydrogen and-   R⁴ is difluoromethyl, trifluoromethyl or methyl and-   R⁵ is hydrogen or fluorine;

and the diastereomers, enantiomers, metabolites, salts, solvates orsolvates of the salts thereof.

Very particular preference is also given to compounds in which

-   R¹ is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl,    3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl,    3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl;-   R² and R³ are both methyl;-   R⁴ is difluoromethyl or trifluoromethyl; and-   R⁵ is hydrogen;

and the diastereomers, enantiomers, metabolites, salts, solvates orsolvates of the salts thereof.

Particular preference is additionally also given to compounds in which

-   R¹ is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl,    3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl,    3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl;-   R² and R³ are both methyl;-   R⁴ is methyl and-   R⁵ is fluorine, where R⁵ is in the ortho position to R⁴;

and the diastereomers, enantiomers, metabolites, salts, solvates orsolvates of the salts thereof.

The present invention especially provides the following compounds:

-   1)    N-[6-(2-Hydroxypropan-2-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide-   2)    N-[6-(Hydroxymethyl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide-   3)    N-[6-(2-Hydroxypropan-2-yl)-2-(3-methoxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide-   4)    N-[6-(Hydroxymethyl)-2-(3-methoxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide-   5)    N-[2-(2-Hydroxyethyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide-   6)    N-[6-(2-Hydroxypropan-2-yl)-2-(3-hydroxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide-   7)    N-[2-(2-Hydroxyethyl)-6-(hydroxymethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide-   8)    N-[6-(2-Hydroxypropan-2-yl)-2-(oxetan-3-ylmethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide-   9)    N-[6-(Hydroxymethyl)-2-(oxetan-3-ylmethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide-   10)    N-{6-(2-Hydroxypropan-2-yl)-2-[3-(methylsulphonyppropyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide-   11)    N-[2-(3-Hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide-   12)    N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide-   13)    6-(Difluoromethyl)-N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]pyridine-2-carboxamide-   14)    6-(Difluoromethyl)-N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-2H-indazol-5-yl}pyridine-2-carboxamide-   15)    6-(Difluoromethyl)-N-[6-(2-hydroxypropan-2-yl)-2-(3-hydroxypropyl)-2H-indazol-5-yl]pyridine-2-carboxamide-   16)    N-[6-(2-Hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide-   17)    N-{6-(2-Hydroxypropan-2-yl)-2-[3-(trifluoromethoxy)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide-   18)    N-{6-(2-Hydroxypropan-2-yl)-2-[3-(2,2,2-trifluoroethoxy)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide-   19)    5-Fluoro-N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-methylpyridine-2-carboxamide-   20)    N-[2-(3-Hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-methylpyridine-2-carboxamide-   21)    6-(2-Hydroxypropan-2-yl)-N-[6-(2-hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)-2H-indazol-5-yl]pyridine-2-carboxamide-   22)    N-{2-[2-(1-Hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide.

The invention further provides a process for preparing compounds of thegeneral formula (III) from compounds of the general formula (II)

in which

-   R¹ is 4,4,4-trifluorobutyl, 3-hydroxy-3-methylbutyl,    3-methoxypropyl, 3-hydroxypropyl, 3-hydroxy-2-methylpropyl,    3-hydroxy-2,2-dimethylpropyl, 3-trifluoromethoxypropyl,    2-methoxyethyl, 2-hydroxyethyl, 2-(methylsulphonyl)ethyl,    3-(methylsulphonyl)propyl or 2-(1-hydroxycyclopropyl) ethyl;-   R⁴ is difluoromethyl, trifluoromethyl or methyl; and-   R⁵ is hydrogen or fluorine;

by the reaction of (II) with appropriately substituted alkyl halides oralkyl 4-methylbenzenesulphonates in the presence of potassium carbonate.

The invention further provides compounds of the general formula (III)

in which

-   R¹ is 4,4,4-trifluorobutyl, 3-hydroxy-3-methylbutyl,    3-methoxypropyl, 3-hydroxypropyl, 3-hydroxybutyl,    3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl,    3-trifluoromethoxypropyl, 2-methoxyethyl, 2-hydroxyethyl,    2-(methylsulphonyl)ethyl, 3-(methylsulphonyl)propyl or    2-(1-hydroxycyclopropyl)ethyl;-   R⁴ is difluoromethyl, trifluoromethyl or methyl; and-   R⁵ is hydrogen or fluorine;

and the diastereomers, enantiomers, metabolites, salts, solvates orsolvates of the salts thereof.

Preference is especially given to the following compounds of the generalformula (III):

methyl5-{[(5-fluoro-6-methylpyridin-2-yl)carbonyl]amino}-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylateand

methyl2-(3-hydroxy-3-methylbutyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate.

The compounds of the general formula (III) are suitable for preparationof a portion of the compounds of the general formula (I).

Furthermore, the compounds of the general formula (III) are inhibitorsof interleukin-1 receptor associated kinase-4 (IRAK4).

The invention further provides a process for preparing the inventivecompounds of the general formula (I) from compounds of the formula (III)

in which

-   R¹ is 4,4,4-trifluorobutyl, 3-hydroxy-3-methylbutyl, 3-hydroxybutyl,    3-methoxypropyl, 3-hydroxypropyl, 3-hydroxy-2-methylpropyl,    3-hydroxy-2,2-dimethylpropyl, 3-trifluoromethoxypropyl,    2-methoxyethyl, 2-hydroxyethyl, 3-(methylsulphonyl)propyl    2-(1-hydroxycyclopropyl)ethyl;-   R² and R³ are methyl;-   R⁴ is difluoromethyl, trifluoromethyl or methyl; and-   R⁵ is hydrogen or fluorine;

by a Grignard reaction with methylmagnesium bromide.

The inventive compounds act as inhibitors of IRAK4 kinase and have anunforeseeable useful pharmacological activity spectrum.

Thus, in addition to the subject matter mentioned above, the presentinvention also provides the use of the inventive compounds for treatmentand/or prophylaxis of diseases in man and animals. Treatment and/orprophylaxis of gynaecological disorders, inflammatory skin disorders,cardiovascular disorders, pulmonary disorders, eye disorders, autoimmunedisorders, pain disorders, metabolic disorders, gout, hepatic disorders,metabolic syndrome, insulin resistance and cancers with the inventiveIRAK4 inhibitors is particularly preferred.

The inventive compounds are suitable for prophylaxis and/or treatment ofvarious disorders and disease-related states, especially disordersmediated by TLR (except TLR3) and/or the IL-1 receptor family and/ordisorders whose pathology is mediated directly by IRAK4.IRAK4-associated disorders include multiple sclerosis, atherosclerosis,myocardial infarction, Alzheimer's disease, virus-induced myocarditis,gout, Vogt-Koyanagi-Harada syndrome, lupus erythematosus, psoriasis,spondyloarthritis and arthritis.

The inventive compounds can also be used for prophylaxis and/ortreatment of disorders mediated by MyD88 and TLR (except for TLR3). Thisincludes multiple sclerosis, rheumatoid arthritis, spondyloarthritis(especially psoriatic spondyloarthritis and Bekhterev's disease),metabolic syndrome including insulin resistance, diabetes mellitus,osteoarthritis, Sjögren syndrome, giant cell arteritis, sepsis, poly-and dermatomyositis, skin disorders such as psoriasis, atopicdermatitis, alopecia areata, acne inversa and acne vulgaris, pulmonarydisorders such as pulmonary fibrosis, chronic obstructive pulmonarydisease (COPD), acute respiratory distress syndrome (ARDS), acute lunginjury (ALI), interstitial lung disease (ILD), sarcoidosis and pulmonaryhypertension.

Because of the mechanism of action of the inventive compounds, they aresuitable for prophylaxis and/or treatment of the TLR-mediated disordersBehçet's disease, gout, endometriosis and endometriosis-associated painand other endometriosis-associated symptoms such as dysmenorrhoea,dyspareunia, dysuria and dyschezia. In addition, the inventive compoundsare suitable for prophylaxis and/or treatment in the case of transplantrejection, lupus erythematosus, adult-onset Still's disease and chronicinflammatory bowel diseases such as ulcerative colitis and Crohn'sdisease.

In addition to the disorders already listed, the use of the inventivecompounds is also suitable for treatment and/or prevention of thefollowing disorders: eye disorders such as keratitis, allergicconjunctivitis, keratoconjunctivitis sicca, macular degeneration anduveitis; cardiovascular disorders such as atherosclerosis, myocardialreperfusion damage, myocardial infarction, hypertension and neurologicaldisorders such as Alzheimer's disease, stroke and Parkinson's.

The mechanism of action of the inventive compounds also enables theprophylaxis and/or treatment of hepatic disorders mediated by TLR andthe IL-1 receptor family, especially NAFLD, NASH, ASH, liver fibrosisand liver cirrhosis.

The prophylaxis and/or treatment of pruritus and pain, especially ofacute, chronic, inflammatory and neuropathic pain, is also provided bythe inventive compounds.

Because of the mechanism of action of the inventive compounds, they aresuitable for prophylaxis and/or treatment of oncological disorders suchas lymphoma, chronic lymphatic leukaemia, melanoma and liver cellcarcinoma, breast cancer, prostate cancer and Ras-dependent tumours.

Moreover, the inventive compounds are suitable for the treatment and/orprevention of disorders mediated via the IL-1 receptor family. Thesedisorders include CAPS (cryopyrin-associated periodic syndromes)including FCAS (familial cold autoinflammatory syndrome), MWS(Muckle-Wells syndrome), NOMID (neonatal-onset multisystem inflammatorydisease) and CONCA (chronic infantile, neurological, cutaneous, andarticular) syndrome, FMF (familial mediterranean fever), HIDS (hyper-IgDsyndrome), TRAPS (tumour necrosis factor receptor 1-associated periodicsyndrome), juvenile idiopathic arthritis, adult-onset Still's disease,Adamantiades-Behçet's disease, rheumatoid arthritis, psoriasis,arthritis, Bekhterev's disease, osteoarthritis, keratoconjunctivitissicca and Sjögren syndrome, multiple sclerosis, lupus erythematosus,alopecia areata, type 1 diabetes mellitus, type 2 diabetes mellitus andthe sequelae of myocardial infarction. Pulmonary disorders such asasthma, COPD, idiopathic interstitial pneumonia and ARDS, gynaecologicaldisorders such as endometriosis and endometriosis-associated pain andother endometriosis-associated symptoms such as dysmenorrhoea,dyspareunia, dysuria and dyschezia, chronic-inflammatory bowel diseasessuch as Crohn's disease and ulcerative colitis are associated withdysregulation of the IL-1 receptor family and are suitable fortherapeutic and/or prophylactic use of the inventive compounds.

The inventive compounds can also be used for treatment and/or preventionof IL-1 receptor family-mediated neurological disorders such as stroke,Alzheimer's disease, craniocerebral trauma, and dermatological disorderssuch as psoriasis, atopic dermatitis, acne inversa, alopecia areata andallergic contact dermatitis.

In addition, the inventive compounds are suitable for the treatmentand/or prophylaxis of pain disorders, especially of acute, chronic,inflammatory and neuropathic pain. This preferably includeshyperalgesia, allodynia, pain from arthritis (such as osteoarthritis,rheumatoid arthritis and spondyloarthritis), premenstrual pain,endometriosis-associated pain, post-operative pain, pain frominterstitial cystitis, CRPS (complex regional pain syndrome), trigeminalneuralgia, pain from prostatitis, pain caused by spinal cord injuries,inflammation-induced pain, lower back pain, cancer pain,chemotherapy-associated pain, HIV treatment-induced neuropathy,burn-induced pain and chronic pain.

The present invention further also provides a method for treatmentand/or prevention of disorders, especially the disorders mentionedabove, using an effective amount of at least one of the inventivecompounds.

In the context of the present invention, the term “treatment” or“treating” includes inhibition, retardation, checking, alleviating,attenuating, restricting, reducing, suppressing, repelling or healing ofa disease, a condition, a disorder, an injury or a health problem, orthe development, the course or the progression of such states and/or thesymptoms of such states. The term “therapy” is understood here to besynonymous with the term “treatment”.

The terms “prevention”, “prophylaxis” and “preclusion” are usedsynonymously in the context of the present invention and refer to theavoidance or reduction of the risk of contracting, experiencing,suffering from or having a disease, a condition, a disorder, an injuryor a health problem, or a development or advancement of such statesand/or the symptoms of such states.

The treatment or prevention of a disease, a condition, a disorder, aninjury or a health problem may be partial or complete.

The inventive compounds can be used alone or, if required, incombination with other active ingredients. The present invention furtherprovides medicaments containing at least one of the inventive compoundsand one or more further active ingredients, especially for treatmentand/or prevention of the abovementioned disorders. Preferred examples ofactive ingredients suitable for combinations include:

General mention may be made of active ingredients such as antibacterial(e.g. penicillins, vancomycin, ciprofloxacin), antiviral (e.g.aciclovir, oseltamivir) and antimycotic (e.g. naftifin, nystatin)substances and gamma globulins, immunomodulatory and immunosuppressivecompounds such as cyclosporin, Methotrexat®, TNF antagonists (e.g.Humira®, Etanercept, Infliximab), IL-1 inhibitors (e.g. Anakinra,Canakinumab, Rilonacept), phosphodiesterase inhibitors (e.g.Apremilast), Jak/STAT inhibitors (e.g. Tofacitinib, Baricitinib,GLPG0634), leflunomid, cyclophosphamide, rituximab, belimumab,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids (e.g. prednisone, prednisolone, methylprednisolone,hydrocortisone, betamethasone), cyclophosphamide, azathioprine andsulfasalazine; paracetamol, non-steroidal anti-inflammatory substances(NSAIDS) (aspirin, ibuprofen, naproxen, etodolac, celecoxib,colchicine). The following should be mentioned for tumour therapy:immunotherapy (e.g. aldesleukin, alemtuzumab, basiliximab, catumaxomab,celmoleukin, denileukin diftitox, eculizumab, edrecolomab, gemtuzumab,ibritumomab tiuxetan, imiquimod, interferon-alpha, interferon beta,interferon-gamma, ipilimumab, lenalidomide, lenograstim, mifamurtide,ofatumumab, oprelvekin, picibanil, plerixafor, poly saccharide-K,sargramostim, sipuleucel-T, tasonermin, teceleukin, tocilizumab),antiproliferative substances, for example but not exclusively amsacrine,arglabin, arsenic trioxide, asparaginase, bleomycin, busulfan,dactinomycin, docetaxel, epirubicin, peplomycin, trastuzumab, rituximab,obinutuzumab, ofatumumab, tositumomab, aromatase inhibitors (e.g.exemestane, fadrozole, formestane, letrozole, anastrozole, vorozole),antioestrogens (e.g. chlormadinone, fulvestrant, mepitiostane,tamoxifen, toremifen), oestrogens (e.g. oestradiol, polyoestradiolphosphate, raloxifen), gestagens (e.g. medroxyprogesterone, megestrol),topoisomerase I inhibitors (e.g. irinotecan, topotecan), topoisomeraseII inhibitors (e.g. amrubicin, daunorubicin, elliptiniumacetate,etoposide, idarubicin, mitoxantrone, teniposide), microtubuli-activesubstances (e.g. cabazitaxel, eribulin, paclitaxel, vinblastine,vincristine, vindesine, vinorelbine), telomerase inhibitors (e.g.imetelstat), alkylating substances and histone deacetylase inhibitors(e.g. bendamustine, carmustine, chlormethine, dacarbazine, estramustine,ifosfamide, lomustine, mitobronitol, mitolactol, nimustineprednimustine, procarbazine, ranimustine, streptozotocin, temozolomide,thiotepa, treosulfan, trofosfamide, vorinostat, romidepsin,panobinostat); substances which affect cell differentation processes,such as abarelix, aminoglutethimide, bexarotene, MMP inhibitors (peptidemimetics, non-peptide mimetics and tetracyclines, for examplemarimastat, BAY 12-9566, BMS-275291, clodronate, prinomastat,doxycycline), mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus,zotarolimus), antimetabolites (e.g. clofarabine, doxifluridine,methotrexate, 5-fluorouracil, cladribine, cytarabine, fludarabine,mercaptopurine, methotrexate, pemetrexed, raltitrexed, tegafur,tioguanine), platinum compounds (e.g. carboplatin, cisplatin,cisplatinum, eptaplatin, lobaplatin, miriplatin, nedaplatin,oxaliplatin); antiangiogenic compounds (e.g. bevacizumab),antiandrogenic compounds (e.g. bevacizumab, enzalutamide, flutamide,nilutamide, bicalutamide, cyproterone, cyproterone acetate), proteasomeinhibitors (e.g. bortezomib, carfilzomib, oprozomib, ONYX0914),gonadoliberin agonists and antagonists (e.g. abarelix, buserelin,deslorelin, ganirelix, goserelin, histrelin, triptorelin, degarelix,leuprorelin), methionine aminopeptidase inhibitors (e.g. bengamidederivatives, TNP-470, PPI-2458), heparanase inhibitors (e.g. SST0001,PI-88); inhibitors against genetically modified Ras protein (e.g.farnesyl transferase inhibitors such as lonafarnib, tipifarnib), HSP90inhibitors (e.g. geldamycin derivatives such as17-allylaminogeldanamycin, 17-demethoxygeldanamycin (17AAG), 17-DMAG,retaspimycin hydrochloride, IPI-493, AUY922, BIIB028, STA-9090,KW-2478), kinesin spindle protein inhibitors (e.g. SB715992, SB743921,pentamidine/chlorpromazine), MEK (mitogen-activated protein kinasekinase) inhibitors (e.g. trametinib, BAY 86-9766 (refametinib),AZD6244), kinase inhibitors (e.g.: sorafenib, regorafenib, lapatinib,Sutent®, dasatinib, cetuximab, BMS-908662, GSK2118436, AMG 706,erlotinib, gefitinib, imatinib, nilotinib, pazopanib, roniciclib,sunitinib, vandetanib, vemurafenib), hedgehog signalling inhibitors(e.g. cyclopamine, vismodegib), BTK (Bruton's tyrosine kinase) inhibitor(e.g. ibrutinib), JAK/pan-JAK (Janus kinase) inhibitor (e.g. SB-1578,baricitinib, tofacitinib, pacritinib, momelotinib, ruxolitinib, VX-509,AZD-1480, TG-101348), PI3K inhibitor (e.g. BAY 1082439, BAY 80-6946(copanlisib), ATU-027, SF-1126, DS-7423, GSK-2126458, buparlisib,PF-4691502, BYL-719, XL-147, XL-765, idelalisib), SYK (spleen tyrosinekinase) inhibitors (e.g. fostamatinib, Excellair, PRT-062607), p53 genetherapy, bisphosphonates (e.g. etidronate, clodronate, tiludronate,pamidronate, alendronic acid, ibandronate, risedronate, zoledronate).For combination, the following active ingredients should also bementioned by way of example but not exclusively: rituximab,cyclophosphamide, doxorubicin, doxorubicin in combination with oestrone,vincristine, chlorambucil, fludarabin, dexamethasone, cladribin,prednisone, 131I-chTNT, abiraterone, aclarubicin, alitretinoin,bisantrene, calcium folinate, calcium levofolinate, capecitabin,carmofur, clodronic acid, romiplostim, crisantaspase, darbepoetin alfa,decitabine, denosumab, dibrospidium chloride, eltrombopag, endostatin,epitiostanol, epoetin alfa, filgrastim, fotemustin, gallium nitrate,gemcitabine, glutoxim, histamine dihydrochloride, hydroxycarbamide,improsulfan, ixabepilone, lanreotide, lentinan, levamisole, lisuride,lonidamine, masoprocol, methyltestosterone, methoxsalen, methylaminolevulinate, miltefosine, mitoguazone, mitomycin, mitotane,nelarabine, nimotuzumab, nitracrin, omeprazole, palifermin, panitumumab,pegaspargase, PEG epoetin beta (methoxy-PEG epoetin beta),pegfilgrastim, peg interferon alfa-2b, pentazocine, pentostatin,perfosfamide, pirarubicin, plicamycin, poliglusam, porfimer sodium,pralatrexate, quinagolide, razoxane, sizofirane, sobuzoxan, sodiumglycididazole, tamibarotene, the combination of tegafur and gimeraciland oteracil, testosterone, tetrofosmin, thalidomide, thymalfasin,trabectedin, tretinoin, trilostane, tryptophan, ubenimex, vapreotide,yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer

Also suitable for tumour therapy is a combination of a non-drug therapysuch as chemotherapy (e.g. azacitidine, belotecan, enocitabine,melphalan, valrubicin, vinflunin, zorubicin), radiotherapy (e.g. I-125seeds, palladium-103 seed, radium-223 chloride) or phototherapy (e.g.temoporfin, talaporfin) which is accompanied by a drug treatment withthe inventive IRAK4 inhibitors or which, after the non-drug tumourtherapy such as chemotherapy, radiotherapy or phototherapy has ended,are supplemented by a drug treatment with the inventive IRAK4inhibitors.

In addition to those mentioned above, the inventive IRAK4 inhibitors canalso be combined with the following active ingredients:

active ingredients for Alzheimer's therapy, for exampleacetylcholinesterase inhibitors (e.g. donepezil, rivastigmine,galantamine, tacrine), NMDA (N-methyl-D-aspartate) receptor antagonists(e.g. memantine); L-DOPA/carbidopa (L-3,4-dihydroxyphenylalanine), COMT(catechol-O-methyltransferase) inhibitors (e.g. entacapone), dopamineagonists (e.g. ropinirole, pramipexole, bromocriptine), MAO-B(monoaminooxidase-B) inhibitors (e.g. selegiline), anticholinergics(e.g. trihexyphenidyl) and NMDA antagonists (e.g. amantadine) fortreatment of Parkinson's; beta-interferon (IFN-beta) (e.g. IFN beta-1b,IFN beta-1a Avonex® and Betaferon®), glatiramer acetate,immunoglobulins, natalizumab, fingolimod and immunosuppressants such asmitoxantrone, azathioprine and cyclophosphamide for treatment ofmultiple sclerosis; substances for treatment of pulmonary disorders, forexample beta-2-sympathomimetics (e.g. salbutamol), anticholinergics(e.g. glycopyrronium), methylxanthines (e.g. theophylline), leukotrienereceptor antagonists (e.g. montelukast), PDE-4 (phosphodiesterase type4) inhibitors (e.g. roflumilast), methotrexate, IgE antibodies,azathioprine and cyclophosphamide, cortisol-containing preparations;substances for treatment of osteoarthritis such as non-steroidalanti-inflammatory substances (NSAIDs). In addition to the two therapiesmentioned, methotrexate and biologics for B-cell and T-cell therapy(e.g. rituximab, abatacept) should be mentioned for rheumatoiddisorders, for example rheumatoid arthritis, spondyloarthritis andjuvenile idiopathic arthritis. Neurotrophic substances such asacetylcholinesterase inhibitors (e.g. donepezil), MAO (monoaminooxidase)inhibitors (e.g. selegiline), interferons and anticonvulsives (e.g.gabapentin); active ingredients for treatment of cardiovasculardisorders such as beta-blockers (e.g. metoprolol), ACE inhibitors (e.g.benazepril), angiotensin receptor blockers (e.g. losartan, valsartan),diuretics (e.g. hydrochlorothiazide), calcium channel blockers (e.g.nifedipine), statins (e.g. simvastatin, fluvastatin); anti-diabeticdrugs, for example metformin, glinides (e.g. nateglinide), DPP-4(dipeptidyl peptidase-4) inhibitors (e.g. linagliptin, saxagliptin,sitagliptin, vildagliptin), SGLT2 (sodium/glucose cotransporter 2)inhibitors/ gliflozin (e.g. dapagliflozin, empagliflozin), incretinmimetics (hormone glucose-dependent insulinotropic peptide (GIP) andglucagon-like peptid 1 (GLP-1) analogues/agonists) (e.g. exenatide,liraglutide, lixisenatide), a-glucosidase inhibitors (e.g. acarbose,miglitol, voglibiose) and sulphonylureas (e.g. glibenclamide,tolbutamide), insulin sensitizers (e.g. pioglitazone) and insulintherapy (e.g. NPH insulin, insulin lispro), substances for treatment ofhypoglycaemia, for treatment of diabetes and metabolic syndrome.Lipid-lowering drugs, for example fibrates (e.g. bezafibrate,etofibrate, fenofibrate, gemfibrozil), nicotinic acid derivatives (e.g.nicotinic acid/laropiprant), ezetimib, statins (e.g. simvastatin,fluvastatin), anion exchangers (e.g. colestyramine, colestipol,colesevelam). Active ingredients such as mesalazine, sulfasalazine,azathioprine, 6-mercaptopurine or methotrexate, probiotic bacteria(Mutaflor, VSL#3®, Lactobacillus GG, Lactobacillus plantarum, L.acidophilus, L. casei, Bifidobacterium infantis 35624, Enterococcusfecium SF68, Bifidobacterium longum, Escherichia coli Nissle 1917),antibiotics, for example ciprofloxacin and metronidazole, anti-diarrhoeadrugs, for example loperamide, or laxatives (bisacodyl) for treatment ofchronic inflammatory bowel diseases. Immunosuppressants such asglucocorticoids and non-steroidale anti-inflammatory substances(NSAIDs), cortisone, chloroquine, cyclosporine, azathioprine, belimumab,rituximab, cyclophosphamide for treatment of lupus erythematosus. By wayof example but not exclusively, calcineurin inhibitors (e.g. tacrolimusand ciclosporin), cell division inhibitors (e.g. azathioprine,mycophenolate mofetil, mycophenolic acid, everolimus or sirolimus),rapamycin, basiliximab, daclizumab, anti-CD3 antibodies,anti-T-lymphocyte globulin/anti-lymphocyte globulin for organtransplants. Vitamin D3 analogues, for example calcipotriol, tacalcitolor calcitriol, salicylic acid, urea, ciclosporine, methotrexate,efalizumab for dermatological disorders.

Mention should also be made of medicaments comprising at least one ofthe inventive compounds and one or more further active ingredients,especially EP4 inhibitors (prostaglandin E2 receptor 4 inhibitors), P2X3inhibitors (P2X purinoceptor 3), PTGES inhibitors (prostaglandin Esynthase inhibitors) or AKR1C3 inhibitors (aldo-keto reductase family 1member C3 inhibitors), for treatment and/or prevention of theaforementioned disorders.

The inventive compounds can act systemically and/or locally. For thispurpose, they can be administered in a suitable manner, for example bythe oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal,rectal, dermal, transdermal or conjunctival route, via the ear or as animplant or stent.

The inventive compounds can be administered in administration formssuitable for these administration routes.

Suitable administration forms for oral administration are those whichwork according to the prior art and release the inventive compoundsrapidly and/or in a modified manner and which contain the inventivecompounds in crystalline and/or amorphous and/or dissolved form, forexample tablets (uncoated or coated tablets, for example with gastricjuice-resistant or retarded-dissolution or insoluble coatings whichcontrol the release of the inventive compound), tablets or films/oblateswhich disintegrate rapidly in the oral cavity, films/lyophilizates,capsules (for example hard or soft gelatin capsules), sugar-coatedtablets, granules, pellets, powders, emulsions, suspensions, aerosols orsolutions.

Parenteral administration can be accomplished with avoidance of aresorption step (for example by an intravenous, intraarterial,intracardiac, intraspinal or intralumbar route) or with inclusion of aresorption (for example by an intramuscular, subcutaneous,intracutaneous, percutaneous or intraperitoneal route). Administrationforms suitable for parenteral administration include preparations forinjection and infusion in the form of solutions, suspensions, emulsions,lyophilizates or sterile powders.

For the other administration routes, suitable examples are inhalablemedicament forms (including powder inhalers, nebulizers), nasal drops,solutions or sprays, tablets, films/oblates or capsules for lingual,sublingual or buccal administration, suppositories, ear or eyepreparations, vaginal capsules, aqueous suspensions (lotions, shakingmixtures), lipophilic suspensions, ointments, creams, transdermaltherapeutic systems (e.g. patches), milk, pastes, foams, sprinklingpowders, implants or stents.

Preference is given to oral or parenteral administration, especiallyoral administration.

The inventive compounds can be converted to the administration formsmentioned. This can be accomplished in a manner known per se by mixingwith inert, nontoxic, pharmaceutically suitable excipients. Theseexcipients include carriers (for example microcrystalline cellulose,lactose, mannitol), solvents (e.g. liquid polyethylene glycols),emulsifiers and dispersing or wetting agents (for example sodiumdodecylsulphate, polyoxysorbitan oleate), binders (for examplepolyvinylpyrrolidone), synthetic and natural polymers (for examplealbumin), stabilizers (e.g. antioxidants, for example ascorbic acid),colorants (e.g. inorganic pigments, for example iron oxides) and flavourand/or odour correctants.

The present invention further provides medicaments which comprise atleast one inventive compound, typically together with one or more inert,nontoxic, pharmaceutically suitable excipients, and the use thereof forthe aforementioned purposes.

In general, it has been found to be advantageous in the case ofparenteral administration to administer amounts of about 0.001 to 1mg/kg, preferably about 0.01 to 0.5 mg/kg, of body weight to achieveeffective results. In the case of oral administration the dosage isabout 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg and mostpreferably 0.1 to 10 mg/kg of body weight.

It may nevertheless be necessary in some cases to deviate from thestated amounts, specifically as a function of the body weight, route ofadministration, individual response to the active ingredient, nature ofthe preparation and time or interval over which administration takesplace. Thus in some cases it may be sufficient to manage with less thanthe abovementioned minimum amount, while in other cases the upper limitmentioned must be exceeded. In the case of administration of greateramounts, it may be advisable to divide them into several individualdoses over the day.

The working examples which follow illustrate the invention. Theinvention is not restricted to the examples.

Unless stated otherwise, the percentages in the tests and examples whichfollow are percentages by weight; parts are parts by weight. Solventratios, dilution ratios and concentration data for the liquid/liquidsolutions are based in each case on volume.

Preparation of the Inventive Compounds

The preparation of the inventive compounds is illustrated by thesynthesis schemes which follow.

Starting materials used for synthesis of the inventive compounds arecarboxylic acids (Intermediate V3), which are commercially available orcan be prepared by routes known from the literature or analogously toroutes known from the literature (see, for example, European Journal ofOrganic Chemistry 2003, 8, 1559-1568, Chemical and PharmaceuticalBulletin, 1990, 38, 9, 2446-2458, Synthetic Communications 2012, 42,658-666, Tetrahedron, 2004, 60, 51, 11869-11874) (see, for example,Synthesis Scheme 1). Some carboxylic acids V3 can be prepared proceedingfrom carboxylic esters (Intermediate V2) by hydrolysis (cf., forexample, the reaction of ethyl 6-(hydroxymethyl)pyridine-2-carboxylatewith aqueous sodium hydroxide solution in methanol, WO200411328) or—inthe case of a tert-butyl ester—by reaction with an acid, for examplehydrogen chloride or trifluoroacetic acid (cf., for example, DaltonTransactions, 2014, 43, 19, 7176-7190). The carboxylic acids V3 can alsobe used in the form of their alkali metal salts. The Intermediates V2can optionally also be prepared from the Intermediates V1 which bear achlorine, bromine or iodine as substituent X¹ by reaction in a carbonmonoxide atmosphere, optionally under elevated pressure, in the presenceof a phosphine ligand, for example 1,3-bis(diphenylphosphino)propane, apalladium compound, for example palladium(II) acetate, and a base, forexample triethylamine, with addition of ethanol or methanol in asolvent, for example dimethyl sulphoxide (for preparation methods see,for example, WO2012112743, WO 2005082866, Chemical Communications(Cambridge, England), 2003, 15, 1948-1949, WO200661715). TheIntermediates V1 are either commercially available or can be prepared byroutes known from the literature. Illustrative preparation methods aredetailed in WO 2012061926, European Journal of Organic Chemistry, 2002,2, 327-330, Synthesis, 2004, 10, 1619-1624, Journal of the AmericanChemical Society, 2013, 135, 32, 12122-12134, Bioorganic and MedicinalChemistry Letters, 2014, 24, 16, 4039-4043, US2007185058, WO2009117421.

X¹ is chlorine, bromine or iodine.

R^(d) is methyl, ethyl, benzyl or tert-butyl.

R⁴, R⁵ are each as defined in the general formula (I).

Methyl 5-amino-1H-indazole-6-carboxylate (Intermediate 2) can beobtained proceeding from methyl 1H-indazole-6-carboxylate (Intermediate0) according to Synthesis Scheme 2 by nitration and reduction of thenitro group of Intermediate 1 with hydrogen in the presence of palladiumon charcoal analogously to WO 2008/001883. For preparation of theIntermediates 3 proceeding from Intermediate 2, it is possible to usevarious coupling reagents known from the literature (Amino Acids,Peptides and Proteins in Organic Chemistry, Vol. 3—Building Blocks,Catalysis and Coupling Chemistry, Andrew B. Hughes, Wiley, Chapter12—Peptide-Coupling Reagents, 407-442; Chem. Soc. Rev., 2009, 38, 606).For example, it is possible to use1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride incombination with 1-hydroxy-1H-benzotriazole hydrate (HOBt, WO2012107475;Bioorg. Med. Chem. Lett., 2008 , 18, 2093),(1H-benzotriazol-1-yloxy)(dimethylamino)-N,N-dimethylmethaniminiumtetrafluoroborate (TBTU, CAS 125700-67-6),(dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methanaminium hexafluorophosphate (HATU, CAS148893-10-1), propanephosphonic anhydride (as solution in ethyl acetateor DMF, CAS68957-94-8) or di-1H-imidazol-1-ylmethanone (CDI) as couplingreagents, with addition of a base such as triethylamine orN-ethyl-N-isopropylpropan-2-amine in each case to the reaction mixture.Preference is given to the use of TBTU andN-ethyl-N-isopropylpropan-2-amine in THF.

The substituents R⁴, R⁵ are each as defined in the general formula (I).

Proceeding from the Intermediates 3, it is possible to prepare2-substituted indazole derivatives (Intermediate 4) (see synthesisscheme 3). Useful reactions for this purpose include those withoptionally substituted alkyl chlorides, alkyl bromides, alkyl iodides oralkyl 4-methylbenzenesulphonates. The alkyl halides or alkyl4-methylbenzenesulphonates used are commercially available or can beprepared analogously to routes known from literature (for thepreparation of alkyl 4-methylbenzenesulphonates, one example is thereaction of an appropriate alcohol with 4-methylbenzenesulphonylchloride in the presence of triethylamine or pyridine; see, for example,Bioorganic and Medicinal Chemistry, 2006, 14, 12 4277-4294). Optionally,in the case of use of alkyl chlorides or alkyl bromides, it is alsopossible to add an alkali metal iodide such as potassium iodide orsodium iodide. Bases used may, for example, be potassium carbonate,caesium carbonate or sodium hydride. In the case of reactive alkylhalides, it is also possible in some cases to useN-cyclohexyl-N-methylcyclohexanamine Useful solvents include, forexample, 1-methylpyrrolidin-2-one, DMF, DMSO or THF. Optionally, thealkyl halides or alkyl 4-methylbenzenesulphonates used may havefunctional groups which have optionally been protected with a protectinggroup beforehand (see also P. G. M. Wuts, T. W. Greene, Greene'sProtective Groups in Organic Synthesis, Fourth Edition, ISBN:9780471697541). If, for example, alkyl halides or alkyl4-methylbenzenesulphonates having one or more hydroxyl groups are used,these hydroxyl groups may optionally be protected by atert-butyl(dimethyl)silyl group or a similar silicon-containingprotecting group familiar to those skilled in the art. Alternatively,the hydroxyl groups may also be protected by the tetrahydro-2H-pyran(THP) group or by the acetyl or benzoyl group. The protecting groupsused can then be detached subsequently to the synthesis of Intermediate4, or else after the synthesis of (I). If, for example, atert-butyl(dimethylsilyl) group is used as protecting group, it can bedetached using tetrabutylammonium fluoride in a solvent such as THF, forexample. A THP protecting group can be detached, for example, using4-methylbenzenesulphonic acid (optionally in monohydrate form). Acetylgroups or benzoyl groups can be detached by treatment with aqueoussodium hydroxide solution.

Optionally, the alkyl halides or alkyl 4-methylbenzenesulphonates usedmay contain functional groups which can be converted by oxidation orreduction reactions known to those skilled in the art (see, for example,Science of Synthesis, Georg Thieme Verlag). If, for example, thefunctional group is a sulphide group, this can be oxidized by methodsknown in the literature to a sulphoxide or sulphone group. In the caseof a sulphoxide group, this can likewise be oxidized to a sulphonegroup. For these oxidation steps, it is possible to use, for example,3-chloroperbenzoic acid (CAS 937-14-4) (in this regard, see also, forexample, US201094000 for the oxidation of a2-(methylsulphanyl)ethyl-1H-pyrazole derivative to a2-(methylsulphinyl)ethyl-1H-pyrazole derivative and the oxidation of afurther 2-(methylsulphanyl)ethyl-1H-pyrazole derivative to a2-(methylsulphonyl)ethyl-1H-pyrazole derivative). If the alkyl halidesor tosylates used contain a keto group, this can be reduced by reductionmethods known to those skilled in the art to an alcohol group (see, forexample, Chemische Berichte, 1980, 113, 1907-1920 for the use of sodiumborohydride). These oxidation or reduction steps can be effectedsubsequently to the synthesis of Intermediate 4, or else after thesynthesis of the inventive compounds of the general formula (I).Alternatively, Intermediate 4 can be prepared via Mitsunobu reaction(see, for example, K. C. K. Swamy et. al. Chem. Rev. 2009, 109, 2551 —2651) of Intermediate 3 with optionally substituted alkyl alcohols. Itis possible to utilize various phosphines such as triphenylphosphine,tributylphosphine or 1,2-diphenylphosphinoethane in combination withdiisopropyl azodicarboxylate (CAS 2446-83-5) or further diazenederivatives mentioned in the literature (K. C. K. Swamy et. al. Chem.Rev. 2009, 109, 2551 — 2651). Preference is given to the use oftriphenylphosphine and diisopropyl azodicarboxylate. If the alkylalcohol bears a functional group it is possible—as in the case of theabovementioned reactions with alkyl halides—for known protecting groupstrategies (further pointers can be found in P. G. M. Wuts, T. W.Greene, Greene's Protective Groups in Organic Synthesis, Fourth Edition,ISBN: 9780471697541) and—as in the case of the abovementioned reactionswith alkyl halides—for oxidation or reduction steps to be effectedcorrespondingly to the synthesis of Intermediate 4, or else after thesynthesis of the inventive compounds of the general formula (I).Proceeding from Intermediate 4, inventive compounds of the generalformula (I) where R² and R³ are defined as C₁-C₆-alkyl (where R² and R³have the same definition) may be obtained by a Grignard reaction (cf.,for example, the reaction of a methyl 1H-indazole-6-carboxylatederivative with methylmagnesium bromide in EP 2489663). For the Grignardreaction, it is possible to use alkylmagnesium halides. Particularpreference is given to methylmagnesium chloride or methylmagnesiumbromide in THF or diethyl ether, or else in mixtures of THF and diethylether. Alternatively, proceeding from Intermediate 4, inventivecompounds of the general formula (I) where R² and R³ are defined asC₁-C₆-alkyl (where R² and R³ have the same definition) may be obtainedby a reaction with an alkyllithium reagent (cf., for example, thereaction of a methyl2-amino-4-chloro-1-methyl-1H-benzimidazole-7-carboxylate derivative withisopropyllithium or tert-butyllithium in WO2006116412). Proceeding fromIntermediate 4, it is possible to prepare inventive compounds of thegeneral formula (I) where R² and R³ are defined as H by reduction withlithium aluminium hydride in THF, lithium borohydride in THF or sodiumborohydride in THF, optionally with addition of methanol, or mixtures oflithium borohydride and sodium borohydride.

The substituents R¹, R², R³, R⁴, R⁵ are each as defined in the generalformula (I).

Proceeding from Intermediate 3, Intermediate 5 where R² and R³ aredefined as C₁-C₆-alkyl (where R² and R³ have the same definition) may beobtained by a Grignard reaction (cf., for example, Synthesis Scheme 4).For this purpose, it is possible to use suitable alkylmagnesium halides,for example methylmagnesium chloride or methylmagnesium bromide in THFor in diethyl ether or else in mixtures of THF and diethyl ether.

Proceeding from Intermediate 5, it is then possible to prepare a portion(I-a) of the inventive compounds (I) where R² and R³ are defined asC₁-C₆-alkyl (where R² and R³ have the same definition). For thispurpose, analogously to Synthesis Scheme 3 (preparation of Intermediate3), useful reactions are those of Intermediate 5 with optionallysubstituted alkyl chlorides, alkyl bromides, alkyl iodides or alkyl4-methylbenzenesulphonates. It is possible to use protecting groupstrategies analogously to those described in Synthesis Scheme 3.

Alternatively, for preparation of a portion (I-a) of the inventivecompounds (I) where R² and R³ are defined as C₁-C₆-alkyl (where R² andR³ have the same definition), it is possible to use the Mitsunobureaction of Intermediate 5 with optionally substituted alkyl alcohols(analogously to Synthesis Scheme 3).

If R¹ in the compounds of the formula (I-a) includes a suitablefunctional group, it is optionally possible subsequently, in analogy toSynthesis Scheme 3, to use oxidation or reduction reactions forpreparation of further inventive compounds.

The substituents R¹, R⁴, R⁵ are each as defined in the general formula(I). R² and R³ always have the same definition and are both C₁-C₆-alkyl.

Proceeding from Intermediate 1, it is possible to prepare Intermediate 4in an alternative manner (see Synthesis Scheme 5). First of all,Intermediate 1 is converted to Intermediate 6 by methods as in SynthesisScheme 3 (preparation of Intermediate 4 from Intermediate 3).

Intermediate 6 can then be converted to Intermediate 7 by reduction ofthe nitro group. For example, the nitro group can be reduced withpalladium on carbon under a hydrogen atmosphere (cf., for example,WO2013174744 for the reduction of 6-isopropoxy-5-nitro-1H-indazole to6-isopropoxy-1H-indazol-5-amine) or by the use of iron and ammoniumchloride in water and ethanol (see, for example, also Journal of theChemical Society, 1955, 2412-2419), or by the use of tin(II) chloride(CAS 7772-99-8). The use of iron and ammonium chloride in water andethanol is preferred. The preparation of Intermediate 4 fromIntermediate 7 can be effected analogously to Synthesis Scheme 2(preparation of Intermediate 3 from Intermediate 2).

As described for Synthesis Scheme 3, it is optionally possible to useprotecting group strategies in the case of Synthesis Scheme 5 as well.Optionally, it is additionally possible, proceeding from Intermediate 6or Intermediate 7, as described for Synthesis Scheme 3, to conductoxidation or reduction reactions known to those skilled in the art (cf.,for example Science of Synthesis, Georg Thieme Verlag).

The substituents R¹, R⁴, R⁵ are each as defined in the general formula(I).

Synthesis of the Example Compounds

Abbreviations and Elucidations

-   -   DMF N,N-dimethylformamide    -   DMSO dimethyl sulphoxide    -   THF tetrahydrofuran    -   RT room temperature    -   HPLC high-performance liquid chromatography    -   h hour(s)    -   HCOOH formic acid    -   MeCN acetonitrile    -   min minute(s)    -   UPLC ultrahigh-performance liquid chromatography    -   DAD diode array detector    -   ELSD evaporating light scattering detector    -   ESI electrospray ionization    -   SQD single quadrupole detector    -   CPG core-pulled precision glass    -   NH₃ ammonia

The term sodium chloride solution always means a saturated aqueoussodium chloride solution.

The chemical names of the intermediates and examples were generatedusing the ACD/LABS (Batch Version 12.01.) software.

Methods

In some cases, the inventive compounds and precursors and/orintermediates thereof were analysed by LC-MS.

Method A1: UPLC (MeCN—HCOOH):

Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEHC18 1.7 50×2.1 mm; eluent A: water+0.1% by vol. of formic acid (99%),eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B;flow rate 0.8 ml/min; temperature: 60° C.; injection: 2 μl; DAD scan:210-400 nm; MS ESI+, ESI−, scan range 160-1000 m/z; ELSD.

Method A2: UPLC (MeCN—NH₃):

Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEHC18 1.7 50×2.1 mm; eluent A: water+0.2% by vol. of ammonia (32%), eluentB: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flowrate 0.8 ml/min; temperature: 60° C.; injection: 2 μl; DAD scan: 210-400nm; MS ESI+, ESI−, scan range 160-1000 m/z; ELSD.

Method A3: (LC-MS)

Instrument: Agilent 1290 Infinity LC; column: Acquity UPLC BEH C18 1.750×2.1 mm; eluent A: water+0.05% by vol. of formic acid, eluent B:acetonitrile+0.05% by vol. of formic acid; gradient: 0-1.7 min 2-90% B,1.7-2.0 min 90% B; flow rate 1.2 ml/min; temperature: 60° C.; injection:2 μl; DAD scan: 190-390 nm; MS: Agilent TOF 6230.

Method A4: (LC-MS)

Instrument: Waters Acquity; column: Kinetex (Phenomenex), 50×2 mm;eluent A: water+0.05% by vol. of formic acid, eluent B:acetonitrile+0.05% by vol. of formic acid; gradient: 0-1.9 min 1-99% B,1.9-2.1 min 99% B; flow rate 1.5 ml/min; temperature: 60° C.; injection:0.5 μl; DAD scan: 200-400 nm.

In some cases, the inventive compounds and the precursors and/orintermediates thereof were purified by the following illustrativepreparative HPLC methods:

Method P1: system: Waters Autopurification system: Pump 2545, SampleManager 2767, CFO, DAD 2996, ELSD 2424, SQD; column: XBridge C18 5 μm100×30 mm; eluent A: water+0.1% by vol. of formic acid, eluent B:acetonitrile; gradient: 0-8 min 10-100% B, 8-10 min 100% B; flow: 50ml/min; temperature: room temperature; solution: max. 250 mg/max. 2.5 mlDMSO or DMF; injection: 1×2.5 ml; detection: DAD scan range 210-400 nm;MS ESI+, ESI−, scan range 160-1000 m/z.

Method P2: system: Waters Autopurification system: Pump 254, SampleManager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100; column: XBridge C18 5μm 10×30 mm; eluent A: water+0.2% by vol. of ammonia (32%), eluent B:methanol; gradient: 0-8 min 30-70% B; flow: 50 ml/min; temperature: roomtemperature; detection: DAD scan range 210-400 nm; MS ESI+, ESI−, scanrange 160-1000 m/z; ELSD.

Method P3: system: Labomatic, pump: HD-5000, fraction collector: LABOCOLVario-4000, UV detector: Knauer UVD 2.1S; column: XBridge C18 5 μm100×30 mm; eluent A: water+0.2% by vol. of ammonia (25%), eluent B:acetonitrile; gradient: 0-1 min 15% B, 1-6.3 min 15-55% B, 6.3-6.4 min55-100% B, 6.4-7.4 min 100% B; flow: 60 ml/min; temperature: roomtemperature; solution: max. 250 mg/2 ml DMSO; injection: 2×2 ml;detection: UV 218 nm; Software: SCPA PrepCon5.

Method P4: system: Labomatic, pump: HD-5000, fraction collector: LABOCOLVario-4000, UV detector: Knauer UVD 2.1S; column: Chromatorex RP C18 10μm 125×30 mm; eluent A: water+0.1% by vol. of formic acid, eluent B:acetonitrile; gradient: 0-15 min 65-100% B; flow: 60 ml/min;temperature: room temperature; solution: max. 250 mg/2 ml DMSO;injection: 2×2 ml; detection: UV 254 nm; Software: SCPA PrepCon5.

Method P5: system: Sepiatec: Prep SFC100, column: Chiralpak IA 5 μm250×20 mm; eluent A: carbon dioxide, eluent B: ethanol; gradient:isocratic 20% B; flow: 80 ml/min; temperature: 40° C.; solution: max.250 mg/2 ml DMSO; injection: 5×0.4 mL; detection: UV 254 nm.

Method P6: system: Agilent: Prep 1200, 2× prep pump, DLA, MWD, Gilson:Liquid Handler 215; column: Chiralcel OJ-H 5 μm 250×20 mm; eluent A:hexane, eluent B: ethanol; gradient: isocratic 30% B; flow: 25 ml/min;temperature: 25° C.; solution: 187 mg/8 ml ethanol/methanol; injection:8×1.0 ml; detection: UV 280 nm.

Method P7: system: Labomatic, pump: HD-5000, fraction collector: LABOCOLVario-4000, UV detector: Knauer UVD 2.1S; column: XBridge C18 5 μm100×30 mm; eluent A: water+0.1% by vol. of formic acid, eluent B:acetonitrile; gradient: 0-3 min: 65% B isocratic, 3-13 min: 65-100% B;flow: 60 ml/min; temperature: room temperature; solution: max. 250 mg/2ml DMSO; injection: 2×2 ml; detection: UV 254 nm.

Method P8: system: Agilent: Prep 1200, 2× prep pump, DLA, MWD, Gilson:Liquid Handler 215; column: Chiralpak IF 5 μm 250×20 mm; eluent A:ethanol, eluent B: methanol; gradient: isocratic 50% B; flow: 25 ml/min;temperature: 25° C.; solution: 600 mg/7 ml N,N-dimethylformamide;injection: 10×0.7 ml; detection: UV 254 nm.

In some cases, substance mixtures were purified by column chromatographyon silica gel.

For preparation of some of the inventive compounds and the precursorsand/or intermediates thereof, a column chromatography purification(“flash chromatography”) was conducted on silica gel using Isolera®devices from Biotage. This was done using cartridges from Biotage, forexample the “SNAP Cartridge, KP_SIL” cartridge of different size and“Interchim Puriflash Silica HP 15UM flash column” cartridges fromInterchim of different size.

Starting Materials

Intermediate V2-1

Methyl 6-(2-hydroxypropan-2-yl)pyridine-2-carboxylate

2.00 g (9.26 mmol) of 2-(6-bromopyridin-2-yl)propan-2-ol (CAS638218-78-7) were dissolved in 20 ml of methanol and 20 ml of DMSO.Subsequently, 250 mg of 1,3-bis(diphenylphosphino)propane, 130 mg ofpalladium(II) acetate and 3 ml of triethylamine were added. The reactionmixture was purged three times with carbon monoxide at room temperatureand stirred under a 13 bar carbon monoxide atmosphere for 30 min. Thecarbon monoxide atmosphere was removed by applying a vacuum and themixture was stirred under a 14 bar carbon monoxide atmosphere at 100° C.for 24 h. The autoclave was decompressed, water was added to thereaction mixture, and the reaction mixture was extracted three timeswith ethyl acetate, washed with saturated aqueous sodiumhydrogencarbonate solution and sodium chloride solution, filteredthrough a hydrophobic filter and concentrated. This gave 1.60 g of acrude product.

UPLC-MS (Method A1): R_(t)=0.76 min (UV detector: TIC), mass found195.00.

Intermediate V3-1

Potassium 6-(2-hydroxypropan-2-yl)pyridine-2-carboxylate

1.60 g of the crude product of Intermediate 0-1 were initially chargedin 15 ml of methanol, 0.74 g of potassium hydroxide was added and themixture was stirred at 50° C. for 16.5 h. After concentration, this gave2.1 g of a residue which was used without further purification.

UPLC-MS (Method A1): R_(t)=0.47 min (UV detector: TIC), mass found181.00.

Intermediate 1-1

Methyl 5-nitro-1H-indazole-6-carboxylate

4.60 g (26.1 mmol) of methyl 1H-indazole-6-carboxylate (CAS No:170487-40-8) were dissolved in 120 ml of sulphuric acid (96%) and cooledto −15° C. in a three-neck flask having a CPG stirrer, dropping funneland internal thermometer. Over a period of 15 min, the nitrating acid(10 ml of 96% sulphuric acid in 5 ml of 65% nitric acid), which had beenprepared and cooled beforehand, was added dropwise to this solution.After the dropwise addition had ended, the mixture was stirred for afurther 1 h (internal temperature at −13° C.). The reaction mixture wasadded to ice, and the precipitate was filtered off with suction, washedwith water and dried in a drying cabinet at 50° C. under reducedpressure. 5.49 g of the title compound were obtained.

UPLC-MS (Method A2): R_(t)=0.75 min p MS (ESIpos): m/z=222(M+H)⁺

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=3.87 (s, 3H), 7.96 (s, 1H), 8.44 (s,1H), 8.70 (s, 1H), 13.98 (br. s., 1H).

Intermediate 2-1

Methyl 5-amino-1H-indazole-6-carboxylate

4.40 g (19 8 mmol) of methyl 5-nitro-1H-indazole-6-carboxylate(Intermediate 1-1) were dissolved in 236 ml of methanol and hydrogenatedwith 1.06 g (0.99 mmol) of palladium on activated carbon under standardhydrogen pressure at 25° C. for 3 h. The reaction mixture was filteredthrough Celite, the filter was washed with methanol, and the filtratewas concentrated. 3.53 g of the title compound were obtained.

¹H NMR (300 MHz, DMSO-d6): δ [ppm]=3.85 (s, 3H) 6.01 (s, 2H) 6.98 (s,1H) 7.79-7.91 (m, 1H) 7.99 (s, 1H) 12.84 (br. s., 1H).

Intermediate 3-1

Methyl5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate

4.95 g (25 9 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid wereinitially charged in 45 ml of THF. 9.07 g (28.2 mmol) ofO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate and4.92 ml (28 2 mmol) of N-ethyl-N-isopropylpropan-2-amine were added andthe mixture was stirred at 25° C. for 30 min. Subsequently, 4.50 g (23.5mmol) of methyl 5-amino-1H-indazole-6-carboxylate (Intermediate 2-1)were added and the mixture was stirred at 25° C. for 24 h. The reactionmixture was filtered with suction through a membrane filter and thesolids were washed with THF and with water, and dried in a dryingcabinet overnight. 7.60 g of the title compound were obtained.

UPLC-MS (Method A2): R_(t)=1.16 min

MS (ESIpos): m/z=365 (M+H)⁺

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=3.97 (s, 3H), 8.13-8.27 (m, 2H), 8.30(s, 1H), 8.33-8.45 (m, 1H), 8.45-8.51 (m, 1H), 9.15 (s, 1H), 12.57 (s,1H), 13.44 (s, 1H).

Intermediate 3-2

Methyl5-({[6-(difluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate

2.85 g (23.5 mmol) of 6-(difluoromethyl)pyridine-2-carboxylic acid wereinitially charged in 30 ml of THF. 6.05 g (18.8 mmol) ofO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate and3.3 ml of N-ethyl-N-isopropylpropan-2-amine were added and the mixturewas stirred at room temperature for 10 minutes. Subsequently, 3.00 g (157 mmol) of methyl 5-amino-1H-indazole-6-carboxylate were added and themixture was stirred at room temperature overnight. The reaction mixturewas admixed with water, and the precipitate was filtered off withsuction and washed repeatedly with water and dichloromethane. This gave1.53 g (27% of theory) of the title compound. The phases of the filtratewere separated, the organic phase was concentrated, admixed with alittle dichloromethane and suspended in an ultrasound bath, and theprecipitate was filtered off with suction. This gave a further 1.03 g ofthe title compound.

1H-NMR (first product fraction, 300 MHz, DMSO-d6): δ [ppm]=3.99 (s, 3H),7.09 (t, 1H), 8.00 (d, 1H), 8.21-8.40 (m, 4H), 9.14 (s, 1H), 12.53 (s,1H), 13.44 (s, 1H).

Intermediate 3-3

Methyl5-({[6-(2-hydroxypropan-2-yl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate

2.10 g of potassium 6-(2-hydroxypropan-2-yl)pyridine-2-carboxylate(Intermediate V3-1) were initially charged in 15 ml of THF. 3.69 g (11.5mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate and 2.00 ml of N-ethyl-N-isopropylpropan-2-amine wereadded and the mixture was stirred at room temperature for 15 min.Subsequently, 1.83 g (9.58 mmol) of methyl5-amino-1H-indazole-6-carboxylate (Intermediate 2-1) were added and themixture was stirred at room temperature for 19 h. The mixture wasadmixed with water and ethyl acetate, the undissolved solids werefiltered off, the phases of the filtrate were separated, and the aqueousphase was extracted twice with ethyl acetate, washed with sodiumchloride solution, filtered through a hydrophobic filter, concentratedand purified by column chromatography on silica gel (hexane/ethylacetate). After the solvents had been removed, 1.56 g of the titlecompound were obtained as a yellow foam.

UPLC-MS (Method A1): R_(t)=1.00 min (UV detector: TIC Smooth), massfound 354.00.

1H-NMR (500 MHz,DMSO-d6): δ [ppm]=1.63 (s, 6H), 3.97 (s, 3H), 5.37(s,1H), 7.90-7.95 (m, 1H), 8.03-8.07 (m, 2H), 8.23(s, 1H),8.29 (s, 1H),9.19 (s, 1H), 12.79 (s, 1H), 13.41 (br.s., 1H).

Intermediate 4-1

Methyl2-(oxetan-3-ylmethyl)-5-({[6-(trifluoromethyppyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate

1.00 g (2.66 mmol) of methyl5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate(Intermediate 3-1) was dissolved in 10 ml of DMF and, after addition of1.10 g (7.99 mmol) of potassium carbonate and 221 mg (1.33 mmol) ofpotassium iodide, the mixture was stirred at 25° C. for 30 min. 603 mg(3.99 mmol) of 3-bromomethyloxetane were added, and the mixture wasstirred at 25° C. for 24 h. The reaction mixture was partitioned betweenwater and ethyl acetate. The mixture was extracted twice with ethylacetate, and the combined organic phases were filtered through ahydrophobic filter and concentrated. The residue was purified by columnchromatography on silica gel (hexane/ethyl acetate). 260 mg of the titlecompound were obtained.

UPLC-MS (Method A2): R_(t)=1.24 min

MS (ESIpos): m/z=435(M+H)⁺

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=3.49-3.64 (m, 1H), 3.95 (s, 3H), 4.49(t, 2H), 4.68 (dd, 2H), 4.81 (d, 2H), 8.20 (dd, 1H), 8.35-8.41 (m, 1H),8.43-8.49 (m, 2H), 8.55-8.58 (m, 1H), 9.06 (s, 1H), 12.53 (s, 1H).

Intermediate 4-2

Methyl2-(2-methoxyethyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate

1.00 g (2.75 mmol) of methyl5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate(Intermediate 3-1) was dissolved in 5 ml of DMF, and 387 μl (4.12 mmol)of 2-bromoethyl methyl ether, 1.14 g (8.23 mmol) of potassium carbonateand 228 mg (1.37 mmol) of potassium iodide were added while stirring.The reaction mixture was stirred at 25° C. for 24 h, diluted with waterand extracted twice with ethyl acetate. The combined organic phases werefiltered through a hydrophobic filter and concentrated. The residue waspurified by column chromatography on silica gel (hexane/ethyl acetate).12 mg of the title compound were obtained.

UPLC-MS (Method A1): R_(t)=1.24 min

MS (ESIpos): m/z=423 (M+H)⁺

¹H NMR (400 MHz, DMSO-d6): δ[ppm]=3.24 (s, 3H), 3.86 (t, 2H), 3.96 (s,3H), 4.65 (t, 2H), 8.21 (dd, 1H), 8.35-8.42 (m, 1H), 8.43-8.51 (m, 2H),8.52 (d, 1H), 9.06 (s, 1H), 12.53 (s, 1H).

Intermediate 4-3

Methyl2-(3-methoxypropyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate

1.00 g (2.75 mmol) of methyl5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate(Intermediate 3-1) was dissolved in 5 ml of DMF, and 460 μl (4.12 mmol)of 1-bromo-3-methoxypropane, 1.14 g (8.23 mmol) of potassium carbonateand 228 mg (1.37 mmol) of potassium iodide were added while stirring.The reaction mixture was stirred at 25° C. for 72 h, diluted with waterand extracted twice with ethyl acetate. The combined organic phases werefiltered through a hydrophobic filter and concentrated. The residue waspurified by column chromatography on silica gel (hexane/ethyl acetate).28 mg of the title compound were obtained.

UPLC-MS (Method A1): R_(t)=1.29 min

MS (ESIpos): m/z=437 (M+H)⁺

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=2.17 (quin, 2H), 3.24 (s, 3H),3.33-3.36 (m, 2H), 3.96 (s, 3H), 4.53 (t, 2H), 8.21 (dd, 1H), 8.35-8.42(m, 1H), 8.45-8.49 (m, 2H), 8.54 (d, 1H), 9.06 (s, 1H), 12.54 (s, 1H).

Intermediate 4-4

Methyl2-(3-hydroxy-3-methylbutyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate

Preparation Method 1

930 mg (2.55 mmol) of methyl5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate(Intermediate 3-1), 1.06 g of potassium carbonate and 212 mg ofpotassium iodide were initially charged in 9 ml of DMF and the mixturewas stirred for 15 min. Then 0.62 ml of 4-bromo-2-methylbutan-2-ol wasadded and the mixture was stirred at 60° C. for 16 h. The mixture wasadmixed with water and extracted twice with ethyl acetate, and theextract was washed three times with saturated sodium chloride solution,filtered and concentrated. Column chromatography purification on silicagel (hexane/ethyl acetate) gave 424 mg of the title compound.

UPLC-MS (Method A2): R_(t)=1.21 min (UV detector: TIC), mass found450.00.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.16 (s, 6H) 2.02-2.11 (m, 2H) 3.96(s, 3H) 4.51-4.60 (m, 3H) 8.20 (dd, J=7.83, 1.01 Hz, 1H) 8.39 (s, 1H)8.45 (s, 2H) 8.55 (d, J=0.76 Hz, 1H) 9.05 (s, 1H) 12.52 (s, 1H)

Preparation Method 2

1.95 g (7.03 mmol) of methyl5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate(Intermediate 7-1) were initially charged in 30 ml of THF. 1.48 g (7.73mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid, 2.71 g (8.44mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate and 1.47 ml (8.44 mmol) ofN-ethyl-N-isopropylpropan-2-amine were added and the mixture was stirredat 25° C. for 20.5 h. Water was added, the mixture was extracted threetimes with ethyl acetate and the extracts were washed with sodiumchloride solution, filtered through a hydrophobic filter andconcentrated. The residue was separated by column chromatography onsilica gel (hexane/ethyl acetate gradient). 2.79 g of the title compoundwere obtained.

UPLC-MS (Method A1): R_(t)=1.23 min (UV detector: TIC), mass found450.00.

Intermediate 4-5

Methyl2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate

1.00 g (2.66 mmol, 97%) of methyl5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate(Intermediate 3-1) was initially charged in 50 ml of DMF, 1.10 g (7.99mmol) of potassium carbonate and 221 mg (1.33 mmol) of potassium iodidewere added while stirring, and the mixture was stirred at 25° C. for 30min. Subsequently, 857 μl (3.99 mmol) of(2-bromoethoxy)(tert-butyl)dimethylsilane were added and the mixture wasstirred at 25° C. for 24 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The combined organic phases werefiltered through a hydrophobic filter and concentrated. The residue waspurified by column chromatography on silica gel (hexane/ethyl acetate).400 mg of the title compound were obtained.

UPLC-MS (Method A1): R_(t)=1.58 min

MS (ESIpos): m/z=523(M+H)⁺

¹H NMR (300 MHz, DMSO-d6): δ [ppm]=−0.18-−0.13 (m, 6H), 0.74 (s, 9H),3.96 (s, 3H), 4.08 (t, 2H), 4.57 (t, 2H), 8.15-8.25 (m, 1H), 8.32-8.43(m, 1H), 8.43-8.52 (m, 3H), 9.07 (s, 1H), 12.53 (s, 1H).

Intermediate 4-6

Methyl2-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate

Analogously to Intermediate 4-5, 1.00 g (2.75 mmol) of methyl5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate(Intermediate 3-1) was dissolved in 10 ml of DMF, 1.14 g (8.24 mmol) ofpotassium carbonate and 228 mg (1.37 mmol) of potassium iodide wereadded while stirring, and the mixture was stirred at 25° C. for 30 min.Subsequently, 1.04 g (4.12 mmol) of(3-bromopropoxy)(tert-butyl)dimethylsilane were added and the mixturewas stirred at 25° C. for 24 h. The reaction mixture was filtered andthe filtercake was washed with ethyl acetate. The reaction mixture waspartitioned between water and ethyl acetate and the aqueous phase wasextracted twice with ethyl acetate. The combined organic phases werefiltered through a hydrophobic filter and concentrated. Purification ofthe residue by preparative HPLC gave 428 mg of the title compound.

UPLC-MS (Method A1): R_(t)=1.63 min

MS (ESIpos): m/z=537(M+H)⁺

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=−0.02-0.06 (m, 6H), 0.87 (s, 9H),2.14 (quin, 2H), 3.62 (t, 2H), 3.96 (s, 3H), 4.54 (t, 2H), 8.20 (d, 1H),8.35-8.42 (m, 1H), 8.43-8.48 (m, 3H), 8.49-8.53 (m, 1H), 9.06 (s, 1H).

Intermediate 4-7

Methyl5-({[6-(2-hydroxypropan-2-yl)pyridin-2-yl]carbonyl}amino)-2-(4,4,4-trifluorobutyl)-2H-indazole-6-carboxylate

300 mg (0.80 mmol) of methyl5-({[6-(2-hydroxypropan-2-yl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate(Intermediate 3-3) were initially charged in 4.5 ml of DMF. 287 mg (1.21mmol) of 1,1,1-trifluoro-4-iodobutane and 333 mg of potassium carbonatewere added and the mixture was stirred at 100° C. for 23 h. Water wasadded, and the mixture was extracted three times with ethyl acetate. Themixture was concentrated and the product was purified by preparativeHPLC. This gave 72 mg of the title compound.

UPLC-MS (Method A1): R_(t)=1.26 min (UV detector: TIC), mass found464.17.

Intermediate 4-8

Methyl5-{[(5-fluoro-6-methylpyridin-2-yl)carbonyl]amino}-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate

195 mg (0.46 mmol) of methyl5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate(Intermediate 7-1) were reacted with 78 mg (0.50 mmol) of5-fluoro-6-methylpyridine-2-carboxylic acid analogous to Intermediate4-4 (Preparation Method 2) within 19.5 h. 228 mg of a crude product wereobtained after analogous aqueous workup.

UPLC-MS (Method A1): R_(t)=1.20 min (UV detector: TIC), mass found414.00.

Intermediate 4-9

Methyl2-(3-hydroxy-3-methylbutyl)-5-{[(6-methylpyridin-2-yl)carbonyl]amino}-2H-indazole-6-carboxylate

195 mg (0.45 mmol) of methyl5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate(Intermediate 7-1) were reacted with 70 mg (0.50 mmol) of6-methylpyridine-2-carboxylic acid analogously to preparation ofIntermediate 4-4 (Preparation Method 2) within 19.5 h. 278 mg of thetitle compound as crude product were obtained after analogous aqueousworkup.

UPLC-MS (Method A1): R_(t)=1.14 min (UV detector: TIC), mass found396.00.

Intermediate 4-10

Methyl2-[3-(2,2,2-trifluoroethoxy)propyl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate

A mixture of 250 mg (0.58 mmol) of methyl5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate(Intermediate 3-1), 193 mg (0.88 mmol) of 3-bromopropyl2,2,2-trifluoroethyl ether, 242 mg of potassium carbonate and 145 mg ofpotassium iodide in 3 ml of DMF was stirred at 100° C. for 20 h. Waterwas added, the mixture was extracted with ethyl acetate and the extractwas washed with sodium chloride solution and concentrated. Purificationby preparative HPLC gave 52 mg of the title compound.

UPLC-MS (Method A1): R_(t)=1.39 min (UV detector: TIC), mass found504.12.

Intermediate 4-11

Methyl5-({[6-(difluoromethyl)pyridin-2-yl]carbonyl}amino)-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate

2.00 g of methyl5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate(Intermediate 7-1) were initially charged in 40 ml of THF. 1.50 g of6-(difluoromethyl)pyridine-2-carboxylic acid, 2.78 g ofO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU, CAS Number 125700-67-6) and 1.5 ml ofN-ethyl-N-isopropylpropan-2-amine were added and the mixture was stirredat RT for 24 h. Water was added, the mixture was extracted three timeswith ethyl acetate, and the combined organic phases were washed withsodium chloride solution and filtered through a hydrophobic filter. Themixture was concentrated and the residue was purified by columnchromatography on silica gel (hexane/ethyl acetate). This gave 3.05 g ofthe title compound as a yellow solid.

UPLC-MS (Method A1): Rt=1.15 min (UV detector TIC), mass found 432.00.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.17 (s, 6H), 2.04-2.11 (m, 2H), 3.99(s, 3H), 4.52-4.60 (m, 3H), 7.10 (t, 1H), 8.00 (dd, 1H), 8.28-8.38 (m,2H), 8.44 — 8.47 (m, 1H), 8.56 (d, 1H), 9.05 (s, 1H), 12.49 (s, 1H).

Intermediate 5-1

N-[6-(2-Hydroxypropan-2-yl)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

To a solution, cooled in an ice-water cooling bath, of 1.50 g (4.12mmol) of methyl5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate(Intermediate 3-1) in 20 ml of THF were cautiously added 6.9 ml (5equivalents) of a 3M methylmagnesium bromide solution in diethyl ether.The mixture was stirred while cooling with an ice bath for 1 h and atroom temperature for 19.5 h. Another 2 equivalents of methylmagnesiumbromide solution were added and the mixture was stirred at roomtemperature for a further 24 h. Saturated aqueous ammonium chloridesolution was added and the mixture was stirred and extracted three timeswith ethyl acetate. The combined organic phases were washed with sodiumchloride solution, filtered through a hydrophobic filter andconcentrated. The residue was purified by column chromatography onsilica gel (hexane/ethyl acetate). 763 mg of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.63 (s, 6H), 5.99 (s, 1H), 7.49 (s,1H), 8.06 (s, 1H), 8.14-8.19 (m, 1H), 8.37 (t, 1H), 8.46 (d, 1H), 8.78(s, 1H), 12.32 (s, 1H), 12.97 (s, 1H).

Intermediate 5-2

6-(Difluoromethyl)-N-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]pyridine-2-carboxamide

Analogously to the preparation of Intermediate 5-1, 2.40 g (6.93 mmol)of methyl5-({[6-(difluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate(Intermediate 3-2) in 10 ml of THF were reacted with three portions of3M methylmagnesium bromide solution in diethyl ether (6.9 ml, thenstirring at room temperature for 45 min; 11.6 ml, then stirring at roomtemperature for 2 h; 6.9 ml, then stirring at room temperature for 2 h).After the workup as for Intermediate 5-1, 2.39 g of a crude product wereobtained, which were used further without further purification.

Intermediate 6-1

Methyl 2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazole-6-carboxylate

5.00 g (22.6 mmol) of methyl 5-nitro-1H-indazole-6-carboxylate(Intermediate 1-1) were initially charged in 40 ml of DMF. 5.65 g (33.9mmol) of 4-bromo-2-methylbutan-2-ol, 9.37 g (67.8 mmol) of potassiumcarbonate and 5.63 g (33.9 mmol) of potassium iodide were added and themixture was stirred at 100° C. for 20 h. Water was added, the mixturewas extracted three times with ethyl acetate and the extracts werewashed with sodium chloride solution, filtered through a hydrophobicfilter and concentrated. The residue was purified by columnchromatography on silica gel (hexane/ethyl acetate). The solids obtainedwere stirred with diethyl ether, filtered off with suction, washed withdiethyl ether and dried. 2.49 g of the title compound were obtained.

UPLC-MS (Method A1): R_(t)=0.93 min (UV detector: TIC), mass found307.00.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.15 (s, 6H), 2.02-2.11 (m, 2H), 3.84(s, 3H), 4.54 (s, 1H), 4.58-4.65 (m, 2H), 8.05 (s, 1H), 8.69 (s, 1H),8.86 (s, 1H).

Intermediate 7-1

Methyl 5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate

4.53 g of iron and 217 mg of ammonium chloride were added to 2.49 g(8.10 mmol) of methyl2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazole-6-carboxylate(Intermediate 6-1) in 30 ml of ethanol and 10 ml of water, and themixture was stirred at 90° C. for 21.5 h. The mixture was filteredthrough Celite and washed through with ethanol three times, and thefiltrate was concentrated and the residue was admixed with water.Extraction was effected three times with ethyl acetate (to improve thephase separation, sodium chloride solution was added). The combinedorganic phases were washed with sodium chloride solution, filteredthrough a hydrophobic filter and concentrated. This gave 1.95 g (85% oftheory) of the title compound.

UPLC-MS (Method A1): R_(t)=0.67 min (UV detector: TIC), mass found277.00.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.14 (s, 6H), 1.96-2.08 (m, 2H), 3.85(s, 3H), 4.39-4.51 (m, 3H), 5.81 (s, 2H), 6.80 (s, 1H), 8.05 (s, 1H),8.18 (s, 1H).

WORKING EXAMPLES Example 1N-[6-(2-Hydroxypropan-2-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

75 mg (0.18 mmol) of methyl2-(2-methoxyethyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate(Intermediate 4-2) were dissolved in 500 μl of THF and admixed with 887μl (0.89 mmol) of a 1 M methylmagnesium bromide solution in THF. Thereaction mixture was stirred at 25° C. for 60 min. Subsequently, 1 ml ofa saturated aqueous ammonium chloride solution was added cautiously andthe mixture was filtered. The aqueous phase was extracted twice withethyl acetate, and the organic phases were combined, filtered through ahydrophobic filter and concentrated. The residue was dissolved in 3 mlof DMSO and purified by preparative HPLC. The product-containingfractions were freeze-dried. 20 mg of the title compound were obtained.

UPLC-MS (Method A1): R_(t)=1.08 min

MS (ESIpos): m/z=423 (M+H)⁺

¹H NMR (300 MHz, DMSO-d6): δ [ppm]=1.62 (s, 6H), 3.22 (s, 3H), 3.82 (t,2H), 4.55 (t, 2H), 5.96 (s, 1H), 7.57 (s, 1H), 8.16 (dl H), 8.29-8.42(m, 2H), 8.42-8.50 (m, 1H), 8.71 (s, 1H), 12.36 (s, 1H)

Example 2N-[6-(Hydroxymethyl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

13 mg (0.36 mmol) of lithium aluminium hydride were suspended in 1 ml ofTHF and the mixture was cooled to 0° C. 75 mg (0.17 mmol) of methyl2-(2-methoxyethyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate(Intermediate 4-2) dissolved in 500 μl of THF were added dropwise andthe mixture was stirred at 25° C. for 60 min. The mixture was dilutedwith water and extracted twice with ethyl acetate, and the combinedorganic phases were washed with sodium chloride solution, filteredthrough a hydrophobic filter, concentrated and dried under reducedpressure. This gave 13 mg of the title compound.

UPLC-MS (Method A2): R_(t)=0.99 min

MS (ESIpos): m/z=394 (M+H)⁺

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=3.23 (s, 3H), 3.83 (t, 2H), 4.56 (t,2H), 4.69 (d, 2H), 5.77 (t, 1H), 7.57 (s, 1H), 8.19 (d, 1H), 8.33-8.41(m, 2H), 8.43-8.47 (m, 1H), 8.51 (s, 1H), 11.20 (s, 1H)

Example 3N-[6-(2-Hydroxypropan-2-yl)-2-(3-methoxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

75 mg (0.17 mmol) of methyl2-(3-methoxypropyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate(Intermediate 4-3) were dissolved in 500 μl of THF and admixed with 859μl (0.86 mmol) of a 1 M methylmagnesium bromide solution in THF. Thereaction mixture was stirred at 25° C. for 60 min. Subsequently, 1 ml ofa saturated ammonium chloride solution was added cautiously and themixture was filtered. The aqueous phase was extracted twice with ethylacetate, and the organic phases were combined, filtered through ahydrophobic filter and concentrated. The residue was dissolved in 3 mlof DMSO and purified by preparative HPLC. The product-containingfractions were freeze-dried. 25 mg of the title compound were obtained.

UPLC-MS (Method A1): R_(t)=1.13 min

MS (ESIpos): m/z=437 (M+H)⁺

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=1.62 (s, 6H), 2.14 (quin, 2H), 3.23(s, 3H), 3.26-3.32 (m, 2H), 4.44 (t, 2H), 5.95 (s, 1H), 7.58 (s, 1H),8.16 (d, 1H), 8.31-8.40 (m, 2H), 8.43-8.48 (m, 1H), 8.72 (s, 1H), 12.36(s, 1H).

Example 4N-[6-(Hydroxymethyl)-2-(3-methoxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

13 mg of lithium aluminium hydride were suspended in THF and the mixturewas cooled to 0° C. 75 mg (0.17 mmol) of methyl2-(3-methoxypropyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate(Intermediate 4-3) in THF were added dropwise and the mixture wasallowed to come to room temperature within 30 min. The mixture wasdiluted with water and filtered, the residue was washed with ethylacetate and the filtrate was extracted with ethyl acetate. The combinedethyl acetate phases were washed with sodium chloride solution, filteredthrough a hydrophobic filter and concentrated. The residue was purifiedby preparative HPLC.

¹H NMR (300 MHz, DMSO-d₆): δ [ppm]=2.14 (quin, 2H), 3.23 (s, 3H), 3.29(t, 2H), 4.45 (t, 2H), 4.68 (d, 2H), 5.77 (t, 1H), 7.58 (s, 1H), 8.18(d, 1H), 8.32-8.48 (m, 3H), 8.51 (s, 1H), 11.21 (s, 1H).

Example 5N-[2-(2-Hydroxyethyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

Stage A:

Preparation ofN-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

100 mg (0.19 mmol) of methyl2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate(Intermediate 4-5) were dissolved in 1 ml of THF and admixed with 669 μl(0.67 mmol) of a 1 M methylmagnesium bromide solution in THF. Thereaction mixture was stirred at 25° C. for 60 min. Another 287 μl (0.29mmol) of a 1 M methylmagnesium bromide solution in THF were added andthe mixture was stirred at 25° C. for 3 h. Subsequently, 20 ml of asaturated ammonium chloride solution were added cautiously and themixture was filtered. The aqueous phase was extracted twice with ethylacetate, and the organic phases were combined, dried over magnesiumsulphate, filtered, concentrated and dried under reduced pressure. Thisgave 50 mg ofN-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

UPLC-MS (Method A2): R_(t)=1.51 min

MS (ESIpos): m/z=523(M+H)⁺

¹H NMR (300 MHz, DMSO-d6): δ [ppm]=−0.17-−0.09 (m, 6H), 0.78 (s, 9H),1.62 (s, 6H), 4.04 (t, 2H), 4.47 (t, 2H), 5.98 (s, 1H), 7.57 (s, 1H),8.16 (d, 1H), 8.29 (s, 1H), 8.37 (t, 1H), 8.45 (d, 1H), 8.73 (s, 1H),12.38 (s, 1H).

Stage B:

50 mg (96 μmol) ofN-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6-(hydroxymethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamidewere dissolved in 1.0 ml of THF and admixed with 144 μl (0.14 mmol) of a1 M solution of tetrabutylammonium fluoride in THF. The reaction mixturewas stirred at room temperature for 1 h. The mixture was diluted withwater and extracted twice with ethyl acetate, and the combined organicphases were washed with saturated sodium chloride solution, filteredthrough a hydrophobic filter and concentrated. This gave 36 mg ofN-[2-(2-hydroxyethyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(Example 5).

¹H-NMR (400 MHz, DMSO-d₆): d [ppm]=1.62 (s, 6H), 3.86 (q, 2H), 4.43 (t,2H), 4.95 (t, 1H), 5.94 (s, 1H), 7.57 (s, 1H), 8.16 (dd, 1H), 8.30 (s,1H), 8.37 (t, 1H), 8.45 (d, 1H), 8.72 (s, 1H), 12.36 (s, 1H).

UPLC-MS (Method A2): R_(t)=0.97 min (UV detector: TIC), mass found408.00.

Example 6N-[6-(2-Hydroxypropan-2-yl)-2-(3-hydroxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

Stage A:

Preparation ofN-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

50 mg (0.09 mmol) of methyl2-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate(Intermediate 4-6) were dissolved in 500 μl of THF and admixed with 326μl (0.33 mmol) of a 1 M methylmagnesium bromide solution in THF. Thereaction mixture was stirred at 25° C. for 60 min. Subsequently, 20 mlof a saturated ammonium chloride solution were added cautiously and themixture was extracted twice with ethyl acetate. The combined organicphases were filtered through a hydrophobic filter, concentrated anddried under reduced pressure. The residue was purified by preparativeHPLC. 40 mg ofN-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyflpyridine-2-carboxamidewere obtained.

UPLC-MS (Method A1): R_(t)=1.58 min

MS (ESIpos): m/z=537(M+H)⁺

¹H NMR (300 MHz, DMSO-d6): δ [ppm]=0.02-0.05 (m, 6H), 0.84-0.91 (m, 9H),1.62 (s, 6H), 2.02-2.18 (m, 2H), 3.55-3.62 (m, 2H), 4.45 (t, 2H), 5.96(s, 1H), 7.57 (s, 1H), 8.16 (d, 1H), 8.31 (s, 1H), 8.33-8.42 (m, 1H),8.45 (d, 1H), 8.72 (s, 1H), 12.37 (s, 1H).

Stage B:

37 mg (0.07 mmol) ofN-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamidewere dissolved in 500 μl of THF and admixed with 207 μl (0.21 mmol) of a1 M solution of tetrabutylammonium fluoride in THF. The reaction mixturewas stirred at 25° C. for 2 h. The mixture was diluted with water andextracted twice with ethyl acetate, and the combined organic phases werewashed with saturated sodium chloride solution, filtered andconcentrated. After purification by preparative HPLC, 10 mg ofN-[6-(2-hydroxypropan-2-yl)-2-(3-hydroxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyflpyridine-2-carboxamide(Example 6, contained secondary component) were obtained.

UPLC-MS (Method A2): R_(t)=1.00 min

MS (ESIpos): m/z=423 (M+H)⁺

¹H NMR selected signals (400 MHz, DMSO-d6): δ [ppm]=1.61 (s), 2.00-2.12(m), 3.38 (t, 2H), 4.44 (t, 2H), 4.62 (br. s., 1H), 5.93 (br. s., 1H),7.55 (s, 1H), 8.13 (d, 1H), 8.27-8.38 (m, 2H), 8.43 (d, 1H), 8.71 (s,1H), 12.30 (br. s., 1H).

Example 7N-[2-(2-Hydroxyethyl)-6-(hydroxymethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

Stage A:

N-[2-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-6-(hydroxymethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

100 mg (0.19 mmol) of methyl2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate(Intermediate 4-5) were dissolved in 1 ml of THF and admixed with 191 μl(0.38 mmol) of a 2 M lithium borohydride solution. The mixture was leftto stir at 25° C. for 24 h. 14 mg (0.38 mmol) of sodium borohydride and500 μl of methanol were added, and the mixture was stirred at 25° C. for4 h. Another 14 mg (0.38 mmol) of sodium borohydride were added, and themixture was stirred at 25° C. for 24 h. Water was added cautiously tothe reaction mixture and the organic phase was removed. The mixture wasthen extracted twice with ethyl acetate, and the combined organic phaseswere washed with saturated sodium chloride solution, filtered through ahydrophobic filter and concentrated. The residue was taken up in 2 ml ofDMSO and purified by preparative HPLC. This gave 30 mg ofN-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6-(hydroxymethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide.

UPLC-MS (Method A2): R_(t)=1.44 min

MS (ESIpos): m/z=495(M+H)⁺

¹H NMR (300 MHz, DMSO-d6): δ [ppm]=−0.16-−0.12 (m, 6H), 0.75-0.79 (m,9H), 4.05 (t, 2H), 4.48 (t, 2H), 4.69 (d, 2H), 5.75-5.77 (m, 1H), 7.57(s, 1H), 8.18 (dd, 1H), 8.30-8.33 (m, 1H), 8.38 (t, 1H), 8.45 (d, 1H),8.51 (s, 1H), 11.20 (s, 1H).

Stage B:

33 mg (0.07 mmol) ofN-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6-(hydroxymethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamidewere dissolved in 1 ml of THF and admixed with 100 μl (0.10 mmol) of a 1M solution of tetrabutylammonium fluoride in THF. The reaction mixturewas stirred at 25° C. for 1 h. The mixture was diluted with water andextracted twice with ethyl acetate, and the combined organic phases werewashed with saturated sodium chloride solution, filtered through ahydrophobic filter, concentrated and dried under reduced pressure. 25 mgofN-[2-(2-hydroxyethyl)-6-(hydroxymethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(Example 7) were obtained.

UPLC-MS (Method A2): R_(t)=0.87 min

MS (ESIpos): m/z=381 (M+H)⁺

¹H NMR (300 MHz, DMSO-d6): δ [ppm]=3.87 (q, 2H), 4.44 (t, 2H), 4.69 (d,2H), 4.98 (t, 1H), 5.70-5.81 (m, 1H), 7.57 (s, 1H), 8.11-8.23 (m, 1H),8.31-8.42 (m, 2H), 8.43-8.49 (m, 1H), 8.51 (s, 1H), 11.20 (s, 1H).

Example 8N-[6-(2-Hydroxypropan-2-yl)-2-(oxetan-3-ylmethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

50 mg (0.12 mmol) of methyl2-(oxetan-3-ylmethyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate(Intermediate 4-1) were dissolved in 500 μl of THF and admixed with 576μl (0.58 mmol) of a 1 M methylmagnesium bromide solution in THF. Thereaction mixture was stirred at 25° C. for 60 min. Subsequently, 20 mlof a saturated aqueous ammonium chloride solution were added cautiouslyand the mixture was concentrated. The aqueous phase was extracted twicewith ethyl acetate, and the organic phases were combined, dried overmagnesium sulphate, filtered and concentrated. The residue was dissolvedin 2.0 ml of DMSO and purified by preparative HPLC. Theproduct-containing fractions were freeze-dried. 30 mg of the titlecompound were obtained.

UPLC-MS (Method A2): R_(t)=1.03 min

MS (ESIpos): m/z=435 (M+H)⁺

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=1.62 (s, 6H), 3.45-3.61 (m, 1H), 4.48(t, 2H), 4.66 (dd, 2H), 4.72 (d, 2H), 5.94 (s, 1H), 7.57 (s, 1H), 8.16(d, 1H), 8.33-8.42 (m, 2H), 8.42-8.47 (m, 1H), 8.72 (s, 1H), 12.36 (s,1H).

Example 9N-[6-(Hydroxymethyl)-2-(oxetan-3-ylmethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

75 mg (0.17 mmol) of methyl2-(oxetan-3-ylmethyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate(Intermediate 4-1) were dissolved in 1 ml of a mixture of THF/methanol(1:1), and 8 mg (0.21 mmol) of sodium borohydride were added. Themixture was left to stir at 25° C. for 60 min. The reaction mixture wasconcentrated, and the residue was admixed with water. The suspension wasstirred vigorously for 15 min, and the solids were filtered off withsuction, washed twice with water and twice with diethyl ether, and driedunder reduced pressure. 48 mg of the title compound were obtained.

UPLC-MS (Method A2): R_(t)=0.94 min

MS (ESIpos): m/z=407 (M+H)⁺

¹H NMR (300 MHz, DMSO-d6): δ [ppm]=3.55 (s, 1H), 4.48 (t, 2H), 4.61-4.77(m, 6H), 7.57 (s, 1H), 8.18 (dd, 1H), 8.33-8.49 (m, 3H), 8.51 (s, 1H),11.21 (s, 1H).

Example 10N-{6-(2-Hydroxypropan-2-yl)-2-[3-(methylsulphonyl)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

A mixture of 500 mg (1.32 mmol) ofN-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(Intermediate 5-1), 569 mg of potassium carbonate and 114 mg ofpotassium iodide in 5.0 ml of DMF was stirred at room temperature for 15min. 414 mg of 1-bromo-3-(methylsulphonyl)propane were added and themixture was stirred at room temperature overnight. Water was added, themixture was twice extracted with ethyl acetate and the extracts werewashed with sodium chloride solution and concentrated. The residue waspurified by column chromatography (dichloromethane/methanol gradient).The product fraction was stirred with diethyl ether, filtered and dried.59 mg of the title compound were obtained.

UPLC-MS (Method A2): R_(t)=1.02 min

MS (ESIpos): m/z=485 (M+H)+

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=1.63 (s, 6H), 2.26-2.42 (m, 2H), 2.99(s, 3H), 3.06-3.16 (m, 2H), 4.55 (t, 2H), 5.96 (s, 1H), 7.60 (s, 1H),8.16 (d, 1H), 8.33-8.48 (m, 3H), 8.73 (s, 1H), 12.37 (s, 1H).

Example 11N-[2-(3-Hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

Preparation Method 1

705 mg (1.57 mmol) of methyl2-(3-hydroxy-3-methylbutyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate(Intermediate 4-4) were initially charged in 10 ml of THF and cooled inan ice-water cooling bath. 2.6 ml (5.0 equivalents) of 3Mmethylmagnesium bromide solution (in diethyl ether) were added and themixture was left to stir while cooling with an ice bath for 1 h and atroom temperature for 4.5 h. Another 1 equivalent of the methylmagnesiumbromide solution was added and the mixture was left to stir at roomtemperature for 20.5 h. Another 1 equivalent again of themethylmagnesium bromide solution was added and the mixture was left tostir at room temperature for 22 h. The reaction mixture was admixed withsaturated aqueous ammonium chloride solution, stirred and extractedthree times with ethyl acetate. The combined organic phases were washedwith sodium chloride solution, filtered through a hydrophobic filter andconcentrated. This gave 790 mg of a residue which was purified by meansof preparative HPLC. This gave 234 mg of the title compound and 164 mgof a product fraction which was stirred with diethyl ether. Afterfiltration with suction followed by drying, a further 146 mg of thetitle compound were obtained.

UPLC-MS (Method A1): R_(t)=1.10 min (UV detector: TIC), mass found450.00.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.14 (s, 6H), 1.61 (s, 6H), 1.99-2.08(m, 2H), 4.42-4.55 (m, 3H), 5.93 (s, 1H), 7.56 (s, 1H), 8.15 (dd, 1H),8.32-8.39 (m, 2H), 8.41-8.47 (m, 1H), 8.70 (s, 1H), 12.34 (s, 1H).

Preparation Method 2

A mixture of 500 mg (1.37 mmol) ofN-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(Intermediate 5-1), 569 mg of potassium carbonate and 114 mg ofpotassium iodide in 5 ml of DMF was stirred at room temperature for 15min. 344 mg (1.5 equivalents) of 4-bromo-2-methylbutan-2-ol were addedand the mixture was heated to 100° C. for 2 h. Another 0.5 equivalent of4-bromo-2-methylbutan-2-ol was added and the mixture was stirred at roomtemperature for 16 h. The mixture was admixed with water and extractedtwice with ethyl acetate, and the combined organic phases were washedwith saturated sodium chloride solution and filtered through ahydrophobic filter and concentrated. The residue was purified by columnchromatography purification on silica gel (hexane/ethyl acetate). Thisgave 100 mg of a product fraction which was stirred with diethyl ether.The solid was filtered and dried. 60 mg of the title compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.14 (s, 6H), 1.61 (s, 6H), 1.99-2.07(m, 2H), 4.43-4.52 (m, 3H) 5.94 (s, 1H) 7.57 (s, 1H) 8.15 (dd, 1H)8.33-8.40 (m, 2H), 8.42-8.48 (m, 1H), 8.71 (s, 1H), 12.35 (s, 1H)

Example 12N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

160 mg (0.44 mmol) ofN-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(Intermediate 5-1) were suspended together with 182 mg of potassiumcarbonate and 36 mg of potassium iodide in 1.0 ml of DMF, and themixture was stirred at room temperature for 15 min. Then 123 mg of2-bromoethyl methyl sulphone (0.66 mmol) were added and the mixture wasstirred at room temperature overnight. Water was added, the mixture wasextracted twice with ethyl acetate and the extracts were washed withsaturated aqueous sodium chloride solution, filtered through ahydrophobic filter and concentrated. Purification of the residue bypreparative HPLC gave 20 mg of the title compound.

UPLC (Method A2): R_(t)=1.01 min;

MS (ESIpos): m/z=471 (M+H)+

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.63 (s, 6H), 2.90 (s, 3H), 3.85 (t,2H), 4.86 (t, 2H), 5.97 (s, 1H), 7.59 (s, 1H), 8.13-8.19 (m, 1H), 8.37(s, 1H), 8.41-8.48 (m, 2H), 8.74 (s, 1H), 12.37 (s, 1H).

Example 136-(Difluoromethyl)-N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]pyridine-2-carboxamide

Preparation Method 1

A mixture of 250 mg of6-(difluoromethyl)-N-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]pyridine-2-carboxamide(crude product of Intermediate 5-2), 144 mg of potassium iodide and 239mg of potassium carbonate in 2.5 ml of DMF was stirred at roomtemperature for 15 min. 145 mg (0.87 mmol) of 4-bromo-2-methylbutan-2-olwere added, the mixture was stirred at 110° C. for 3 h, another 96 mg of4-bromo-2-methylbutan-2-ol were added and the mixture was stirred at110° C. for 4 h. Water was added, the mixture was extracted twice withethyl acetate and the extract was washed with semisaturated aqueoussodium chloride solution, filtered through a hydrophobic filter andconcentrated. Purification was effected by column chromatography onsilica gel (hexane/ethyl acetate). 61 mg of the title compound wereobtained.

UPLC-MS (Method A1): R_(t)=1.00 min (UV detector: TIC), mass found432.00.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=1.14 (s, 6H), 1.63 (s, 6H), 1.97-2.08(m, 2H), 4.41-4.55 (m, 3H), 5.99 (s, 1H), 7.03 (t, 1H), 7.56 (s, 1H),7.94 — 8.00 (m, 1H), 8.24-8.38 (m, 3H), 8.71 (s, 1H), 12.49 (s, 1H).

Preparation Method 2

Analogously to the preparation of Example 11 (Preparation Method 1),3.00 g of methyl5-({[6-(difluoromethyl)pyridin-2-yl]carbonyl}amino)-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate(Intermediate 4-11) were reacted with 3M methylmagnesium bromidesolution (in diethyl ether). After purification of the crude product bystirring with diethyl ether, filtering followed by preparative HPLC,1.37 g of the title compound were obtained.

Example 146-(Difluoromethyl)-N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

A mixture of 250 mg of6-(difluoromethyl)-N-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]pyridine-2-carboxamide(crude product of Intermediate 5-2), 144 mg of potassium iodide and 239mg of potassium carbonate in 2.5 ml of DMF was stirred at roomtemperature for 15 min. 162 mg of 2-bromoethyl methyl sulphone (0.87mmol) were added and the mixture was stirred at 110° C. for 3 h. Waterwas added, the mixture was extracted twice with ethyl acetate and theextract was washed with semisaturated aqueous sodium chloride solution,filtered through a hydrophobic filter and concentrated. The residue waspurified by preparative HPLC and the product fractions were additionallypurified by column chromatography purification on silica gel(hexane/ethyl acetate). 40 mg of the title compound were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.65 (s, 6H), 2.90 (s, 3H), 3.85 (t,2H), 4.85 (t, 2H), 6.03 (s, 1H), 7.04 (t, 1H), 7.59 (s, 1H), 7.98 (d,1H), 8.25-8.36 (m, 2H), 8.43 (s, 1H), 8.75 (s, 1H), 12.52 (s, 1H).

Example 156-(Difluoromethyl)-N-[6-(2-hydroxypropan-2-yl)-2-(3-hydroxypropyl)-2H-indazol-5-yl]pyridine-2-carboxamide

Stage A:

Preparation of N-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(difluoromethyl)pyridine-2-carboxamide

A mixture of 250 mg of6-(difluoromethyl)-N-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]pyridine-2-carboxamide(Intermediate 5-2), 48 mg of potassium iodide and 239 mg of potassiumcarbonate in 2.5 ml of DMF was stirred at room temperature for 15 min.219 mg (0.87 mmol, 1.5 equivalents) of(3-bromopropoxy)(tert-butyl)dimethylsilane were added and the mixturewas stirred at 110° C. for 3 h. Another 1 equivalent of(3-bromopropoxy)(tert-butyl)dimethylsilane was added and the mixture wasstirred at 100° C. for 4 h. Water was added, the mixture was extractedwith ethyl acetate and the extract was washed with aqueous sodiumchloride solution, filtered through a hydrophobic filter andconcentrated. The residue was purified by column chromatography(hexane/ethyl acetate). 92 mg of the title compound were obtained.

Stage B:

Analogously to the preparation of Example 6, Stage B, 92 mg ofN-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(difluoromethyl)pyridine-2-carboxamidewere reacted with 0.53 ml of a 1 M solution of tetrabutylammoniumfluoride in THF within 1 h. Aqueous workup as in Example 6 andpurification by preparative HPLC gave 46 mg of the title compound.

UPLC-MS (Method A1): R_(t)=0.92 min (UV detector: TIC), mass found404.00.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.64 (s, 6H), 2.05 (quin, 2H),3.35-3.46 (m, 2H), 4.45 (t, 2H), 4.64 (t, 1H), 5.99 (s, 1H), 7.04 (t,1H), 7.57 (s, 1H), 7.95 — 7.99 (m, 1H), 8.25-8.36 (m, 3H), 8.73 (s, 1H),12.50 (s, 1H).

Example 16N-[6-(2-Hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

A mixture of 210 mg (0.58 mmol) ofN-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(Intermediate 5-1) in 3 ml of DMF was admixed with 0.11 ml (0.87 mmol)of 1,1,1-trifluoro-4-iodobutane and 239 mg of potassium carbonate, andthe mixture was stirred at 80° C. for 6 h. After addition of water, themixture was extracted three times with ethyl acetate, and the combinedorganic phases were washed with saturated sodium chloride solution,filtered through a hydrophobic filter and concentrated. The crudeproduct was purified by preparative HPLC. 19 mg of the title compoundwere obtained.

UPLC-MS (Method A1): R_(t)=1.27 min (UV detector: TIC), mass found474.15.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.62 (s, 6H), 2.10-2.33 (m), 4.49 (t,2H), 5.94 (s, 1H), 7.59 (s, 1H), 8.13-8.18 (m, 1H), 8.32-8.41 (m, 2H),8.41-8.47 (m, 1H), 8.72 (s, 1H), 12.35 (s, 1H).

Example 17N-{6-(2-Hydroxypropan-2-yl)-2-[3-(trifluoromethoxy)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

150 mg (0.33 mmol) ofN-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(Intermediate 5-1) were initially charged in 2 ml of THF. 58 mg (0.40mmol) of 3-(trifluoromethoxy)propan-l-ol, 131 mg of triphenylphosphineand 71 μl of diisopropyl azodicarboxylate (DIAD, CAS 2446-83-5) wereadded and the mixture was stirred at room temperature for 19 h. 0.83 mlof sodium hydroxide solution (2M) was added and the mixture was stirredat 40° C. for 5 h. The mixture was diluted with water and extractedthree times with ethyl acetate, and the combined organic phases wereconcentrated and purified by preparative HPLC. 16 mg of the titlecompound were obtained as a crude product.

UPLC-MS (Method A2): R_(t)=1.26 min (UV detector: TIC), mass found490.14.

¹H-NMR (400 MHz, DMSO-d₆, selected signals): δ [ppm]=1.61 (s, 6H), 1.84(d, 1H), 2.32 (quint., 2H), 4.08 (t, 2H), 4.51 (t, 2H), 7.58 (s, 1H),8.15 (d, 1H), 8.31 — 8.39 (m, 2H), 8.44 (d, 1H), 8.72 (s, 1H), 12.35 (s,1H).

Example 18N-{6-(2-Hydroxypropan-2-yl)-2-[3-(2,2,2-trifluoroethoxy)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

Analogously to the preparation of Example 11 (Preparation Method 1), 52mg (0.10 mmol) of methyl2-[3-(2,2,2-trifluoroethoxy)propyl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate(Intermediate 4-10) in 3 ml of THF were reacted with 2×171 μl of 3Mmagnesium bromide solution in diethyl ether. Purification by preparativeHPLC gave 12 mg of the title compound.

UPLC-MS (Method A1): R_(t)=1.25 min (UV detector: TIC), mass found504.16.

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm]=1.63 (s, 6H), 2.20(quin, 2H), 3.58(t,2H),4.05(q, 2H), 4.47(t, 2H),5.94(s, 1H), 7.58 (s, 1H), 8.15 (dd, 1H),8.32 (s, 1H), 8.36 (t, 1H), 8.45(d, 1H), 8.73 (s, 1H), 12.36 (s,1H).

Example 195-Fluoro-N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-methylpyridine-2-carboxamide

228 mg (0.31 mmol) of methyl 5 -{[(5-fluoro-6-methylpyridin-2-yl)carbonyl]amino}-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate(Intermediate 4-8) were initially charged in 4.5 ml of THF and cooledwith an ice cooling bath. 0.63 ml of 3M methylmagnesium bromide solution(in diethyl ether) was added and the mixture was left to stir whilecooling with an ice bath for 2 h and at room temperature for 21 h. Thereaction mixture was admixed with saturated aqueous ammonium chloridesolution and extracted three times with ethyl acetate. The combinedorganic phases were concentrated. The residue was purified bypreparative HPLC. 82 mg of the title compound were obtained.

UPLC-MS (Method A2): R_(t)=1.03 min (UV detector: TIC), mass found414.21.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.13 (s, 6H), 1.63 (s, 6H), 1.99-2.05(m, 2H), 2.55-2.59 (m, 3H), 4.42-4.50 (m, 3H), 5.95 (s, 1H), 7.54 (s,1H), 7.83 (t, 1H), 8.05 (dd, 1H), 8.31 (s, 1H), 8.68 (s, 1H), 12.33 (s,1H).

Example 20N-[2-(3-Hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-methylpyridine-2-carboxamide

278 mg (0.48 mmol) of methyl2-(3-hydroxy-3-methylbutyl)-5-{[(6-methylpyridin-2-yl)carbonyl]amino}-2H-indazole-6-carboxylate(Intermediate 4-9) were initially charged in 5.0 ml of THF and cooledwith an ice cooling bath. 0.97 ml of 3M methylmagnesium bromide solution(in diethyl ether) was added and the mixture was left to stir whilecooling with an ice bath for 2 h and at room temperature for 20.5 h.Another 0.48 ml of 3M methylmagnesium bromide solution was added and themixture was left to stir at room temperature for 67 h. The mixture wasadmixed with saturated aqueous ammonium chloride solution and extractedthree times with ethyl acetate, and the extracts were washed with sodiumchloride solution, filtered through a hydrophobic filter andconcentrated. The residue was purified by preparative HPLC. 111 mg ofthe title compound were obtained.

UPLC-MS (Method A2): R_(t)=0.97 min (UV detector: TIC), mass found396.22.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.15 (s, 6H), 1.64 (s, 6H), 2.00-2.08(m, 2H), 2.61 (s, 3H), 4.41-4.59 (m, 3H), 5.92 (s, 1H), 7.50 (dd, 1H),7.56 (s, 1H), 7.90-7.99 (m, 2H), 8.33 (s, 1H), 8.70 (s, 1H), 12.39 (s,1H).

Example 216-(2-Hydroxypropan-2-yl)-N-[6-(2-hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)-2H-indazol-5-yl]pyridine-2-carboxamide

A solution of 72 mg (0.16 mmol) of methyl5-({[6-(2-hydroxypropan-2-yl)pyridin-2-yl]carbonyl}amino)-2-(4,4,4-trifluorobutyl)-2H-indazole-6-carboxylate(Intermediate 4-7) in 10 ml of THF was cooled in an ice/water coolingbath. 0.26 ml of 3M methylmagnesium bromide solution in diethyl etherwas added and the mixture was stirred for 2 h and then at roomtemperature for 20 h. Another 1 equivalent of the 3M methylmagnesiumbromide solution was added and the mixture was stirred at roomtemperature for 24 h. Saturated aqueous ammonium chloride solution wasadded, the mixture was three times extracted with ethyl acetate and theextracts were washed with sodium chloride solution and concentrated.Preparative HPLC gave 22 mg (31% of theory) of the title compound.

UPLC-MS (Method A2): R_(t)=1.15 min (UV detector: TIC), mass found464.20.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.56 (s, 6H), 1.64 (s, 6H), 2.07-2.34(m, 4H), 4.49 (t, 2H), 5.32 (s, 1H), 6.05 (s, 1H), 7.60 (s, 1H), 7.87(dd, 1H), 7.99-8.05 (m, 2H), 8.35 (s, 1H), 8.79 (s, 1H), 12.45 (s, 1H).

Example 22N-{2-[2-(1-Hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

250 mg (0.69 mmol) ofN-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(Intermediate 5-1) were initially charged in 5 ml of DMSO. 159 mg (0.96mmol) of 1-(2-bromoethyl)cyclopropanol, 285 mg of potassium carbonateand 171 mg of potassium iodide were added and the mixture was stirred at100° C. for 5 h. Water was added and the mixture was extracted threetimes with ethyl acetate. The combined organic phases were washed withsodium chloride solution, filtered through a hydrophobic filter andconcentrated. The residue was purified by preparative HPLC (column:Waters XBridge C18 5μ 100×30 mm, eluent A: water+0.1% by volume offormic acid (99%), eluent B: acetonitrile). Freeze-drying gave 45 mg ofthe title compound.

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm]=0.18-0.22 (m, 2H), 0.48-0.52 (m, 2H),1.62 (s, 6H), 2.08 (t, 2H), 4.54-4.60 (m, 2H), 5.36 (s, 1H), 5.96 (s,1H), 7.57 (s, 1H), 8.16 (dd, 1H), 8.34-8.39 (m, 2H), 8.45 (d, 1H), 8.72(s, 1H), 12.36 (s, 1H).

Assessment of Physiological Efficacy

IRAK4 Kinase Assay

The IRAK4-inhibitory activity of the inventive substances was measuredin the IRAK4 TR-FRET assay (TR-FRET=Time Resolved Fluorescence ResonanceEnergy Transfer) described hereinafter.

Recombinant fusion protein from N-terminal GST (glutathioneS-transferase) and human IRAK4, expressed in baculovirus-infected insectcells (Hi5, BTI-TN-5B1-4, cell line purchased from Invitrogen, catalogueNo. B855-02) and purified via affinity chromatography, was used asenzyme. The substrate used for the kinase reaction was the biotinylatedpeptide biotin-Ahx-KKARFSRFAGSSPSQASFAEPG (C-terminus in amide form)which can be purchased, for example, from Biosyntan GmbH (Berlin-Buch).

For the assay, 11 different concentrations in the range from 20 μM to0.073 nM were prepared from a 2 mM DMSO solution of the test substance.50 nl of the respective solution were pipetted into a black low-volume384-well microtitre plate (Greiner Bio-One, Frickenhausen, Germany), 2μl of a solution of IRAK4 in assay buffer [50 mM HEPES pH 7.5, 5 mMMgC12, 1.0 mM dithiothreitol, 30 μM activated sodium orthovanadate, 0.1%(w/v) of bovine gamma-globulin (BGG) 0.04% (v/v) nonidet-P40 (Sigma)]were added and the mixture was incubated for 15 min to allow prebindingof the substances to the enzyme prior to the kinase reaction. The kinasereaction was then started by addition of 3 μl of a solution of adenosinetriphosphate (ATP, 1.67 mM=final concentration in 5 μl of assay volume:1 mM) and peptide substrate (0.83 μM=final concentration in 5 μl assayvolume: 0.5 μM) in assay buffer, and the resulting mixture was incubatedat 22° C. for the reaction time of 45 min. The concentration of theIRAK4 was adjusted to the respective activity of the enzyme and set suchthat the assay was carried out in the linear range. Typicalconcentrations were in the order of about 0.2 nM. The reaction wasstopped by addition of 5 μl of a solution of TR-FRET detection reagents[0.1 μM streptavidin-XL665 (Cisbio Bioassays; France, catalogue No.610SAXLG)] and 1.5 nM anti-phosphoserine antibody [Merck Millipore, “STKAntibody”, catalogue No. 35-002] and 0.6 nM LANCE EU-W1024-labelledanti-mouse-IgG antibody (Perkin-Elmer, product No. AD0077;alternatively, it is possible to use a terbium cryptate-labelledanti-mouse-IgG antibody from Cisbio Bioassays) in aqueous EDTA solution(100 mM EDTA, 0.4% [w/v] bovine serum albumin [BSA] in 25 mM HEPES pH7.5).

The resulting mixture was incubated at 22° C. for 1 h to allow formationof a complex of the biotinylated phosphorylated substrate and thedetection reagents. The amount of the phosphorylated substrate was thenevaluated by measuring the resonance energy transfer from europiumchelate-labelled anti-mouse-IgG antibody to streptavidin-XL665. To thisend, the fluorescence emissions at 620 nm and 665 nm were measured afterexcitation at 350 nm in a TR-FRET measuring instrument, for example aRubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux(Perkin-Elmer). The ratio of the emissions at 665 nm and 622 nm wastaken as a measure of the amount of phosphorylated substrate. The datawere normalized (enzyme reaction without test substance=0% inhibition;all other assay components but no enzyme=100% inhibition). Typically,the test substances were tested on the same microtitre plates at 11different concentrations in the range from 20 μM to 0.073 nM (20 μM, 5.7μM, 1.6 μM, 0.47 μM, 0.13 μM, 38 nM, 11 nM, 3.1 nM, 0.89 nM, 0.25 nM and0.073 nM). The dilution series were prepared prior to the assay (2 mM to7.3 nM in 100% DMSO) by serial dilutions. The ICso values werecalculated by a 4-parameter fit.

TABLE 1 IC₅₀ values of the example compounds in the IRAK4 kinase assayIC₅₀ Example [nM] 1 30.6 2 135.6 3 7.2 4 52.7 5 264.5 6 35.7 7 867.3 815.0 9 103.8 10 18.5 11 3.4 12 10.7 13 1.3 14 10.8 15 12.3 16 21.5 1736.0 18 47.5 19 8.9 20 13.3 21 117.2 22 3.7

The inhibitory activity of the inventive substances of the generalformula (III) with respect to IRAK4 was likewise measured in the IRAK4TR-FRET assay described above. The following are mentioned by way ofexample: the compound Intermediate 4-2 with an IC₅₀=21.7 nM,Intermediate 4-3 with an IC₅₀=13.0 nM and Intermediate 4-4 with anIC₅₀=6.2 nM.

TNF-α Secretion in THP-1 Cells

This test is suited to test substances for their ability to inhibitsecretion of TNF-α (tumour necrosis factor alpha) in THP-1 cells (humanmonocytic acute leukaemia cell line). TNF-α is a cytokine involved ininflammatory processes. In this test, TNF-α secretion is triggered byincubation with bacterial lipopolysaccharide (LPS).

THP-1 cells were kept in continuous suspension cell culture [RPMI 1460medium with L-Glutamax (Gibco, Cat. No. 61870-044) supplemented withfoetal calf serum (FCS) 10% (Invitrogen, Cat. No. 10082-147), 1%penicillin/streptomycin (Gibco BRL, Cat. No. 15140-114)] and should notexceed a cell concentration of 1×10⁶cells/ml. The assay was carried outin cell culture medium (RPMI 1460 medium with L-Glutamax supplementedwith FCS 10%).

In each case 2-2.5 μl of the cell suspension (corresponds to 4000 cells)per well were dispensed into a 384-well test plate (Greiner, Cat. No.784076), in each of which 40-50 nl substance had been dissolved in 100%DMSO. This was done using 10 different concentrations in the range from20 μM to 0.073 nM for each substance. The cells were incubated at roomtemperature for 15 min. 2-2.5 μl of 0.1 μg/ml LPS (Sigma, Escherichiacoli 055:B5, Cat. No. L5418) dissolved in cell culture medium (finalconcentration 0.05 μg/ml) were then dispensed into each well. As neutralcontrol, cells were treated with 0.05 μg/ml LPS and 1% DMSO and, asinhibitor control, with 1% DMSO only.

The plates were centrifuged at 80 g for 30 s and incubated at 37° C., 5%CO₂ and 95% atmospheric humidity for 17 h. The amount of TNF-α wasdetermined using the TNF-alpha HTRF Detection Kit (Cisbio, Cat. No.62TNFPEB/C). To this end, 2 μl of the detection solution in each case,consisting of anti-TNF-α-XL665 conjugate and anti-TNF-α-cryptateconjugate dissolved in the reconstitution buffer in accordance with themanufacturer's instructions, were added for the HTRF (HomogeneousTime-Resolved Fluorescence) test. After the addition, the mixture wasincubated either at room temperature for 3 h or at 4° C. overnight. Thesignals were then read at 620/665 nm using an HTRF-enabled measuringinstrument such as the BMG PheraStar.

The activity of the substances is expressed as the ratio between neutraland inhibitor control in per cent. The IC₅₀ values were calculated usinga 4-parameter fit.

TABLE 2 IC₅₀ values of the example compounds with respect to thesecretion of TNF-α in THP-1 cells IC₅₀ Example [μM] 1 1.0 2 15.1 3 0.7 45.6 5 5.4 6 0.9 7 16.4 8 1.0 9 6.5 10 1.0 11 0.2 12 0.3 13 0.1 14 0.2 150.2 16 0.2 17 0.5 18 0.3 19 0.1 20 0.2 21 1.8

In Vitro LPS (Lipopolysaccharide)-Induced Cytokine Production in HumanPBMCs (Peripheral Blood Mononuclear Cells)

The effect of the inventive compounds of the general formula (I) oninduced cytokine production in human PBMCs was examined Cytokineproduction was induced here by LPS, a TLR4 ligand, which leads toactivation of the IRAK4-mediated signal path.

The human PBMCs were obtained from anti-coagulated human whole blood.For this purpose, 15 ml of Ficoll-Paque (Biochrom, Cat. No. L6115) wereinitially pipetted in Leucosep tubes and 20 ml of human blood wereadded. After centrifugation of the blood at 800 g for 15 min at roomtemperature, the plasma including the platelets was removed anddiscarded. The PBMCs were transferred into centrifugation tubes and madeup with PBS (phosphate-buffered saline) (Gibco, Cat. No. 14190). Thecell suspension was centrifuged at room temperature at 250 g for 10 minand the supernatant was discarded. The PBMCs were resuspended incomplete medium (RPMI 1640, without L-glutamine (PAA, Cat. No. E15-039),10% FCS; 50 U/ml penicillin, 50 μg/ml streptomycin (PAA, Cat. No.P11-010) and 1% L-glutamine (Sigma, Cat. No. G7513)).

The assay was also carried out in complete medium. The PBMCs were seededin 96-well plates at a cell density of 2.5×10⁵ cells/well. The inventivecompounds were subjected to serial dilution in a constant volume of 100%DMSO and used in the assay at 8 different concentrations in the rangefrom 10 μM to 3 nM such that the final DMSO concentration was 0.4% DMSO.Prior to the actual stimulation, the cells were then pre-incubatedtherewith for 30 min. To induce cytokine secretion, the cells werestimulated with 0.1 μg/ml LPS (Sigma, Escherichia coli 0128:B12, Cat.No. L2887) for 24 hours. Cell viability was determined using theCellTiter-Glo luminescent assay (Promega, Cat. No. G7571 (G755/G756A))in accordance with the manufacturer's instructions. The amount ofsecreted TNF-α in the cell culture supernatant was determined using theHuman ProInflammatory 9-Plex Tissue Culture Kit (MSD, Cat. No. K15007B)in accordance with the instructions of the manufacturer. By way ofexample, Example Compound 11 and Example Compound 12 have activity ≤1μM.

In Vitro TLR-4/TLR-7-Induced Interleukin (IL)-23 Secretion of HumanDendritic Cells (DCs)

The effect of the inventive compounds of the general formula (I) on theinduced production of the pro-inflammatory cytokine IL-23 which plays anessential role for the generation of TH-17 cells was examined in humanDCs. It is stated that TH-17 cells play a crucial role in thepathogenesis of disorders such as rheumatoid arthritis, psoriaticarthritis, Bekhterev's disease (ankylosing spondylitis) or else multiplesclerosis (Lubberts, Nat. Rev. Rheumatol., 2015; Marinoni et al., Auto.Immun Highlights, 2014; Isailovic et al., J. Autoimmun , 2015; Staschkeet al., J Immunol., 2009). To detect the effect of the inventivecompounds on IL-23 production, human primary monocytes (isolated fromhuman PBMCs using magnetic separation [Miltenyi Biotech, MonocyteIsolation Kit, Cat. No. 130-091-153] and by the addition of growthfactors (recombinant human GM-CSF [PeproTech, Cat. No. 300-03] and IL-4[PeproTech, Cat. No. 200-04]) in complete medium (VLE (very lowendotoxin) RPMI 1640 [Biochrom AG, Cat. No. FG1415], 10% Fetal BovineSerum (FBS) [Gibco, Cat-No. 10493-106]; 50 μM β-mercaptoethanol (Gibco,Cat. No. 31350], 50 U/ml penicillin and streptomycin [Gibco, Cat. No.15140-114]) were differentiated in culture over 6 days to DCs. After theDCs had been harvested, they were resuspended in complete medium andseeded in a cell density of 2×10⁵ cells/well in a 96-well plate (Costar,Cat. No. 3599). The inventive compounds were subjected to serialdilution in a constant volume of 100% DMSO and used in the assay at 9different concentrations in the range from 10 μM to 1 nM. It was ensuredhere that the DMSO concentration present was always 0.1% DMSO for eachof the 9 concentrations used. There was a 30-minute preincubation of theDCs with the inventive compounds. Thereafter, the DCs were stimulated toproduce IL-23 by the addition of 10 ng/ml LPS (Sigma, Escherichia coliserotype 0127:B8, Cat. No. L3129) (TLR4 ligand) and 2.5 μg/ml of TLR-7/8ligand R848 (Invivogen, Cat. No. tlrl-r848-5), both activate theIRAK4-mediated signalling pathway, in an incubator (37° C., 95% rH, 5%CO₂) for 24 hours. After this incubation time of 24 hours, thesupernatants were harvested and analysed using a commercially availablehIL-23 ELISA (eBiosciences, Cat. No. 88-7237-88), which was conductedaccording to the manufacturer's instructions. The results of theinhibition of IL-23 in human DCs are shown by way of example for ExampleCompound 12 in FIG. 1 .

In Vitro TLR-7/8- or TLR-9-Induced IFNα Production of Human PlasmacytoidDendritic Cells (pDCs)

With the aid of this test, the effect of the inventive compounds of thegeneral formula (I) on the production of IFNα (interferon-alpha) inhuman pDCs, a key cytokine in the pathogenesis of systemic lupuserythematosus (Mathian et al., Arthritis Rheum, 2009; Crow M. K., RheumDis Clin N Am, 2010), can be studied. For this purpose, human PBMCs wereisolated from whole blood as described above and the plasmacytoid DCs(pDCs) were isolated therefrom using a commercially available cellseparation kit (Miltenyi Biotech, Plasmacytoid Dendritic Cell IsolationKit II, Cat. No. 130-097-415). The obtained pDCs were resuspended incomplete medium (RPMI 1640+GlutaMax [Gibco, Cat. No. 61870-010]supplemented with 10% FBS [Gibco, Cat. No. 10493-106] and 50 Upenicillin/streptomycin [Gibco, Cat. No. 15140-114]) and seeded at acell density of 5×10⁴ cells/well in a 96-well microtitre plate (Costar,Cat. No. 3599). The inventive compounds were subjected to serialdilution in a constant volume of 100% DMSO and used in the assay at 9different concentrations in the range from 10 μM to 1 nM. It was ensuredthat the DMSO concentration present was always 0.1% DMSO for each of the9 concentrations tested. There was a 30-minute preincubation of the pDCswith the inventive compounds. The pDCs were stimulated either with aTLR7/8 ligand (imiquimod, R837, Invivogen, Cat. No. tlrl-imq) or with aTLR-9 ligand (CPG-A, ODN2216, Invivogen, Cat. No. tlrl-2216-1) and thisled to activation of the IRAK4-mediated signalling pathways. Afterincubation for 24 hours, the cell culture supernatants were removed andanalysed using a commercially available human IFNα ELISA (IFNalphaMulti-Subtype ELISA Kit, pbl Assay Science, Cat. No. 41105-1). Theresults of the inhibition of IFNα in human plasmacytoid DCs are shown byway of example for Example Compound 12 in FIG. 2A and FIG. 2B.

In Vivo Model of TLR-Mediated Inflammation

The inventive compounds of the general formula (I) were examined fortheir in vivo efficacy in a model of in vivo TLR-mediated inflammation.This mechanistic model particularly shows the potential effect of theinventive compounds on TLR4-mediated disorders, since an LPS-mediatedinflammation model was used. In this model, female Balb/c mice (about 8weeks old; Charles River Laboratories, Germany) were divided into groupsof 5 animals each. The control group was treated with the vehicle inwhich the substance had been dissolved (substance vehicle) and also withthe vehicle in which the LPS had been dissolved. The substance treatmentgroups as well as the positive control group received 0.2 mg LPS/kg bodyweight (Sigma, Cat. No. L4391) (lipopolysaccharides from E. coli0111:B4) intraperitoneally (i.p.). In addition, the positive controlgroup was treated with the substance vehicle described above. Thesubstance was administered orally 16 hours before induction ofinflammation by administration of LPS. To examine the effect of theinventive compounds on the inflammation, blood samples were taken fromthe animals after 1.5 hours. The concentration of particular cytokinesin the plasma was determined using the Mouse

ProInflammatory 7-Plex Tissue Culture Kit (MSD, Cat. No. K15012B) inaccordance with the manufacturer's instructions. IRAK4 inhibitors areeffective in the TLR-mediated inflammation model. FIG. 3 shows theamount of TNF-α in the plasma, which is reduced in a dose-dependentmanner by administration of Example Compound 11 in comparison with theLPS-induced concentration.

In Vivo Model of IL-1β-Mediated Inflammation

To evaluate the potential efficacy of the inventive compounds of thegeneral formula (I) in IL-1β-mediated disorders, IL-1β was administeredi.p. to female Balb/c mice (about 8 weeks old, Charles RiverLaboratories, Germany) and the effect of the inventive compounds onIL-1β-mediated cytokine secretion was examined There were 5 animals ineach group. The control group was treated with the vehicles used fordissolving the substance and the IL-1β. The substance treatment groupsand the positive control group were each administered 90 μg IL-1β/kgbody weight i.p. (R&D, Cat. No. 401-ML/CF). The substance or its vehiclein the positive control group was administered 6 hours before theadministration of IL-1β. 2 hours after administration of the IL-1β,TNF-α was determined in the plasma isolated from the blood using theMouse Prolnflammatory 7-Plex Tissue Culture Kit (MSD, Cat. No. K15012B)in accordance with the manufacturer's instructions. Administration ofIL-1β led to an elevated TNF-α plasma concentration which was inhibitedby treatment with Example Compounds 11 and 12. This is illustrated byFIG. 4A and FIG. 4B.

In Vivo Adjuvant-Induced Arthritis Model

To determine the anti-inflammatory activity of the inventive compoundsof the general formula (I), they were examined for their in vivoefficacy in an arthritis model. For this purpose, male Lewis rats (about100-125 g, Charles River Laboratories, Germany) were each administered100 μl of a complete Freund's adjuvant (CFA) solution (M. tuberculosisH37Ra [Difo Lab, Cat. No. -231141] dissolved in Incomplete Freund'sadjuvant [Difco Lab, Cat. No. -263910]) into the tailhead subcutaneouslyon day 0. There were n=8 rats in each group. Both a healthy controlgroup and a disease control group were included in the study. Eachcontrol group was given p.o. treatment only with the vehicle of the testsubstance. The treatment with different dosages of the test substancewas conducted in a preventative manner, i.e. starting from day 0, byoral administration. On day 0, the starting condition of the animals wasadditionally determined in terms of the disease activity scores (ratingof the severity of arthritis based on a points system). Here, pointswere awarded according to the extent of joint inflammation from 0 to 4for the presence of an erythema including joint swelling (0=none;1=slight; 2=moderate; 3=distinct; 4=severe) for both hind paws and addedup. To determine the anti-inflammatory efficacy of the compounds, thedisease activity of the animals was scored by means of disease activityscoring starting from day 8, when the animals first exhibit signs ofarthritis, and subsequently 3 times per week, until the end (day 20).Statistical analysis was performed using single-factor variance analysis(ANOVA) and by comparison with the control group by means of multiplecomparative analysis (Dunnett's test).

The s.c. administration of CFA in rats leads to acute arthritis withdistinct joint inflammation in rats. This induced arthritis wasinhibited by the treatment with Example Compound 11. This is illustratedby FIG. 5 .

In Vivo Collagen Antibody-Induced Arthritis Model in Mice

The anti-inflammatory effect of the inventive compounds of the generalformula (I) was examined in a further murine arthritis model. For thispurpose, female Balb/c mice (about 9 weeks old, Charles RiverLaboratories, Kingston, Canada) were each injected intravenously on day0 with 200 μl of a collagen antibody cocktail (10 mg/ml; ArthritoMab, MDBioproducts) into the tail vein (except for the healthy control groupincluded in the study). On day 6, these mice then each received afurther intraperitoneal injection of 200 μl of LPS. There were n=10 micein each group. Both a healthy control group and a disease control groupwere included in the study. Each control group was given p.o. treatmentonly with the vehicle of the test substance. The treatment withdifferent dosages of the test substance was conducted in a preventativemanner, i.e. starting from day 0, by oral administration. Over thecourse of the experiment, the extent of disease was scored on the basisof a point award system for the disease activity score on all four paws.In this awarding of points, no points are awarded for a healthy paw,whereas points from 1 [mild inflammation, for example, of the toe(s)] to4 [severe inflammation extending over the entire paw] are awarded ineach case for the particular extent of joint inflammation that hasarisen from the toes through the metatarsal joint to the ankle joint, asexplained as follows:

-   -   0=normal    -   1=erythema and mild swelling limited to the tarsal or ankle or        toes    -   2=erythema and mild swelling extending from the ankle to the        metatarsus (2 segments)    -   3=erythema and moderate swelling extending from the ankle as far        as the metatarsal joints    -   4=erythema and severe swelling encompassing the metatarsus, foot        and toes

For this parameter, the starting condition was determined beforehand oneday before the start of the experiment (day −1) and this diseaseactivity score was subsequently scored three times per week from day 8onwards. Statistical analysis was performed using single-factor varianceanalysis (ANOVA) and by comparison with the control group by means ofmultiple comparative analysis (Dunnett's test).

The i.v. administration of a collagen antibody cocktail including thesubsequent i.p. administration of LPS in mice leads to acute arthritiswith distinct joint inflammation. This induced arthritis was inhibitedby the treatment with Example Compound 12. This is illustrated by FIG. 6.

In Vivo NASH Mouse Model

To experimentally induce NASH, 200 μg streptozotocin (STZ;Sigma-Aldrich, USA) is each injected subcutaneously in 45 male 2-day-oldC57BL/6 mice. Starting at 4 weeks of age, these animals are fed adlibitum with a high-fat diet (HFD; 57 kcal% fat, #HFD32 from CLEA,Japan). At an age of 6 weeks, the animals are randomized into 3 groups(15 animals per group). While one of the groups does not receive anytreatment, the other 2 groups are daily orally treated either withvehicle or the test substance over 4 weeks. After the 4-week treatment,all animals are sacrificed painlessly under anaesthesia, and the liversare removed and fixed for the histological study in Bouin's solution (H.Denk, “Fixierung histologischer Praparate” [Fixing of HistologicalPreparations], in: P. Bock (ed.): “Romeis Mikroskopische Technik”[Romei's Microscopy Techniques], Urban & Schwarzenberg,Munich-Vienna-Baltimore 1989, 17th edition, page 97, ISBN3-541-11227-1). Thereafter, the liver samples are embedded in paraffinand 5 μm-thick paraffin sections are produced. Histological sections ofeach liver are stained a) for the determination of the NAFLD activityscore (NAS) with haematoxylin-eosin (HC), and b) for the determinationof liver fibrosis with Picro-Sirius red (Waldeck, Germany). The NAFLDactivity score is determined in the haematoxylin-eosin sections on thebasis of the criteria recommended by D.E. Kleiner et al., Hepatology 41(2005), 1313-1321 (Table 1). For the histological quantification offibrotic areas, 5 digital photos (DFC280; Leica, Germany) are taken foreach section under 200-fold microscope enlargement and the percentage offibrosis is determined using the ImageJ Software (National Institute ofHealth, USA).

In Vivo db/db Mouse Model

30 male 8-week-old db/db mice are used. This model is a well acceptedmodel for obesity, insulin resistance and type 2 diabetes (Aileen J FKing; The use of animal models in diabetes research; British Journal ofPharmacology 166 (2012), 877-894). During the experiment, the animalsreceive a standard diet (RM1(E) 801492, SDS) and tap water ad libitum.The animals are randomized into 3 groups (10 animals per group) andtreated orally with the test substance over 6 weeks. During the studyperiod, blood is taken from the animals at different time points (beforestart of treatment, 3 weeks after start of treatment and 2 days beforethe end of treatment) to determine insulin sensitivity parameters (e.g.HbA1c, glucose content, insulin content). In addition, an OGTT (oralglucose tolerance test) as a parameter for determination of insulinsensitivity is conducted 1 day before start of treatment and 2 daysafter the end of treatment. In addition, the HOMA-IR index (fastinginsulin level (mU/l)*fasting glucose level (mmol/l)/22.5) is calculated.

In Vivo B-Cell Lymphoma-Associated Xenotransplantation Model

The anti-tumour activity of the inventive compounds of the generalformula (I) is studied in murine xenotransplantation models. For thispurpose, female C.B-17 SCID mice are implanted subcutaneously with humanB-cell lymphoma cell lines, e.g. TMD-8. At a mean tumour size of 20-30mm², oral monotherapeutic treatment is started with an inventivecompound or by administration of an inventive compound in combinationwith a standard therapy, each administered orally. However, the animalsare randomized beforehand. The treatment is ended as soon as theuntreated control group has large tumours. The tumour size and bodyweight are determined three times per week. Decreases in body weight area measure of treatment-related toxicity (>10%=critical, stoppage intreatment until recovery, >20%=toxic, termination). The tumour area isdetected by an electronic caliper gauge [length (mm)×width (mm)] At theend of the study, the tumour weight is also determined. The anti-tumourefficacy defines the ratio of tumour weight of treatment vs. control(T/C) [tumour weight of the treatment group on day x/tumour weight ofthe control group on day x] or the ratio of the tumour area of treatmentvs. control [tumour area of the treatment group on day x/tumour area ofthe control group on day x]. A compound having a T/C greater than 0.5 isdefined as active (effective). Statistical analysis is preformed usingsingle-factor ANOVA and by comparison with the control group by means ofpair-by-pair comparative analysis (Dunnett's test).

1-23. (canceled)
 24. A method for treating a dermatological disease ordisorder in a human in need thereof, comprising administering to thehuman an effective amount of a compound of formula (I):

wherein: R¹ is C₁-C₆-alkyl, wherein the C₁-C₆-alkyl group ismonosubstituted with an R⁷SO₂ or R⁷SO group, or wherein the C₁-C₆-alkylgroup is polysubstituted with at least one of an R⁷SO₂ group or R⁷SOgroup, and one or more additional substituents selected from the groupconsisting of halogen, hydroxyl, an unsubstituted or mono- orpoly-halogen substituted C₃-C₆-cycloalkyl, an R⁶ group, and an R⁸Ogroup; R² and R³ always have the same definition and are both eitherhydrogen or C₁-C₆-alkyl; R⁴ is halogen, cyano, an unsubstituted or asingly or multiply, identically or differently substituted C₁-C₆-alkylor an unsubstituted or a singly or multiply, identically or differentlysubstituted C₃-C₆-cycloalkyl, and the substituents are selected from thegroup consisting of halogen and hydroxyl; R⁵ is hydrogen, halogen or anunsubstituted or mono- or poly-halogen-substituted C₁-C₆-alkyl; R⁶ is anunsubstituted or mono- or di-methyl-substituted monocyclic saturatedheterocycle having 4 to 6 ring atoms, which contains a heteroatom or aheterogroup from the group of O, S, SO and SO₂; R⁷ is C₁-C₆-alkyl, wherethe C₁-C₆-alkyl group is unsubstituted or mono- or polysubstitutedidentically or differently by halogen, hydroxyl or C₃-C₆-cycloalkyl; orR⁷ is C₃-C₆-cycloalkyl; and R⁸ is C₁-C₆-alkyl, where the C₁-C₆-alkylgroup is unsubstituted or mono- or polysubstituted identically ordifferently by halogen, or a diastereomer, an enantiomer, a salt, asolvate, or a solvate of the salt thereof.
 25. The method according toclaim 24, wherein: R^(1l) is C₁-C₆-alkyl, wherein the C₁-C₆-alkyl groupis monosubstituted with an R⁷SO₂ group or an R⁷SO group, or wherein theC₁-C₆-alkyl group is polysubstituted with at least one of an R⁷SO₂ groupor an R⁷SO group, and one or more additional substituents selected fromthe group consisting of fluorine, hydroxyl, an R⁶ group, and an R⁸Ogroup; R² and R³ always have the same definition and are both eitherhydrogen or C₁-C₃-alkyl; R⁴ is halogen, cyano or C₁-C₃-alkyl, whereinthe C₁-C₃-alkyl group is unsubstituted or mono- or polysubstitutedidentically or differently by halogen or hydroxyl; R⁵ is hydrogen,fluorine, chlorine or C₁-C₃-alkyl; R⁶ is oxetanyl or tetrahydrofuranyl;R⁷ is C₁-C₄-alkyl, wherein the C₁-C₄-alkyl group is unsubstituted ormonosubstituted by hydroxyl or by cyclopropyl or substituted by threefluorine atoms, and R⁸ is an unsubstituted C₁-C₄-alkyl group or atri-fluorine-substituted C₁-C₄-alkyl group.
 26. The method according toclaim 24, wherein R⁴ is difluoromethyl, trifluoromethyl or methyl. 27.The method according to claim 24, wherein R⁵ is hydrogen or fluorine.28. The method according to claim 24, wherein R² and R³ are both eitherhydrogen or methyl.
 29. The method according to claim 25, wherein R¹ isC₂-C₆-alkyl, wherein the C₂-C₆-alkyl group is monosubstituted by anR⁷SO₂ group; R² and R³ always have the same definition and are botheither hydrogen or methyl; R⁴ is an unsubstituted or mono- orpoly-halogen-substituted C₁-C₃-alkyl group or a C₁-C₃-alkyl groupsubstituted by one hydroxyl group or a C₁-C₃-alkyl group substituted byone hydroxyl group and three fluorine atoms; R⁵ is hydrogen, fluorine orC₁-C₃-alkyl, and R⁷ is C₁-C₃-alkyl.
 30. The method according to claim29, wherein R¹ is a methyl-SO₂-substituted C₂-C₄-alkyl group; R² and R³always have the same definition and are both either hydrogen or methyl;R⁴ is selected from the group consisting of methyl, ethyl,trifluoro-C₁-C₃-alkyl, difluoro-C₁-C₃-alkyl, hydroxymethyl,1-hydroxyethyl, 2-hydroxypropan-2-yl and 2,2,2-trifluoro-1-hydroxyethyl,and R⁵ is hydrogen, fluorine or methyl.
 31. The method according toclaim 30, wherein R¹ is 2-(methyl sulphonyl)ethyl or3-(methylsulphonyl)propyl; R² and R³ are both either methyl or hydrogen;R⁴ is difluoromethyl, trifluoromethyl or methyl; and R⁵ is hydrogen orfluorine.
 32. The method according to claim 31, wherein R¹ is3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl; R² and R³ areboth methyl; R⁴ is difluoromethyl or trifluoromethyl; and R⁵ ishydrogen.
 33. The method according to claim 31, wherein R¹ is3-(methylsulphonyl)propyl or 2-(methyl sulphonyl)ethyl; R² and R³ areboth methyl; R⁴ is methyl; and R⁵ is fluorine, wherein R⁵ is in theortho position to R⁴.
 34. The method according to claim 24, wherein thecompound is:

or a diastereomer, an enantiomer, a metabolite, a salt, a solvate, asolvate of the salt thereof.
 35. The method according to claim 24,wherein the compound is:

or a salt thereof.
 36. The method according to claim 24, wherein thedermatological disease or disorder is psoriasis, atopic dermatitis,Kindler's syndrome, bullous pemphigoid, allergic contact dermatitis,alopecia areata, acne inversa or acne vulgaris.
 37. The method accordingto claim 24, wherein the dermatological disease or disorder ispsoriasis, atopic dermatitis, allergic contact dermatitis, or acneinversa.
 38. The method according to claim 24, wherein thedermatological disease or disorder is atopic dermatitis.
 39. The methodaccording to claim 34, wherein the dermatological disease or disorder ispsoriasis, atopic dermatitis, Kindler's syndrome, bullous pemphigoid,allergic contact dermatitis, alopecia areata, acne inversa or acnevulgaris.
 40. The method according to claim 34, wherein thedermatological disease or disorder is psoriasis, atopic dermatitis,allergic contact dermatitis, or acne inversa.
 41. The method accordingto claim 34, wherein the dermatological disease or disorder is atopicdermatitis.
 42. The method according to claim 35, wherein thedermatological disease or disorder is psoriasis, atopic dermatitis,Kindler's syndrome, bullous pemphigoid, allergic contact dermatitis,alopecia areata, acne inversa or acne vulgaris.
 43. The method accordingto claim 35, wherein the dermatological disease or disorder ispsoriasis, atopic dermatitis, allergic contact dermatitis, or acneinversa.
 44. The method according to claim 35, wherein thedermatological disease or disorder is atopic dermatitis.
 45. The methodaccording to claim 24, wherein the compound is administered to the humanin a dosage form comprising at least one pharmaceutically suitableexcipient.
 46. The method according to claim 34, wherein the compound isadministered to the human in a dosage form comprising at least onepharmaceutically suitable excipient.
 47. The method according to claim35, wherein the compound is administered to the human in a dosage formcomprising at least one pharmaceutically suitable excipient.